894 results on '"PDL1"'
Search Results
2. Autologous patient-derived exhausted nano T-cells exploit tumor immune evasion to engage an effective cancer therapy
- Author
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José L. Blaya-Cánovas, Carmen Griñán-Lisón, Isabel Blancas, Juan A. Marchal, César Ramírez-Tortosa, Araceli López-Tejada, Karim Benabdellah, Marina Cortijo-Gutiérrez, M. Victoria Cano-Cortés, Pablo Graván, Saúl A. Navarro-Marchal, Jaime Gómez-Morales, Violeta Delgado-Almenta, Jesús Calahorra, María Agudo-Lera, Amaia Sagarzazu, Carlos J. Rodríguez-González, Tania Gallart-Aragón, Christina Eich, Rosario M. Sánchez-Martín, and Sergio Granados-Principal
- Subjects
Biomimetic nanoparticles ,Immune evasion ,PD1 ,PDL1 ,T-cell exhaustion ,Immune checkpoint ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Active targeting by surface-modified nanoplatforms enables a more precise and elevated accumulation of nanoparticles within the tumor, thereby enhancing drug delivery and efficacy for a successful cancer treatment. However, surface functionalization involves complex procedures that increase costs and timelines, presenting challenges for clinical implementation. Biomimetic nanoparticles (BNPs) have emerged as unique drug delivery platforms that overcome the limitations of actively targeted nanoparticles. Nevertheless, BNPs coated with unmodified cells show reduced functionalities such as specific tumor targeting, decreasing the therapeutic efficacy. Those challenges can be overcome by engineering non-patient-derived cells for BNP coating, but these are complex and cost-effective approaches that hinder their wider clinical application. Here we present an immune-driven strategy to improve nanotherapeutic delivery to tumors. Our unique perspective harnesses T-cell exhaustion and tumor immune evasion to develop a groundbreaking new class of BNPs crafted from exhausted T-cells (NExT) of triple-negative breast cancer (TNBC) patients by specific culture methods without sophisticated engineering. Methods NExT were generated by coating PLGA (poly(lactic-co-glycolic acid)) nanoparticles with TNBC-derived T-cells exhausted in vitro by acute activation. Physicochemical characterization of NExT was made by dynamic light scattering, electrophoretic light scattering and transmission electron microscopy, and preservation and orientation of immune checkpoint receptors by flow cytometry. The efficacy of chemotherapy-loaded NExT was assessed in TNBC cell lines in vitro. In vivo toxicity was made in CD1 mice. Biodistribution and therapeutic activity of NExT were determined in cell-line- and autologous patient-derived xenografts in immunodeficient mice. Results We report a cost-effective approach with a good performance that provides NExT naturally endowed with immune checkpoint receptors (PD1, LAG3, TIM3), augmenting specific tumor targeting by engaging cognate ligands, enhancing the therapeutic efficacy of chemotherapy, and disrupting the PD1/PDL1 axis in an immunotherapy-like way. Autologous patient-derived NExT revealed exceptional intratumor accumulation, heightened chemotherapeutic index and efficiency, and targeted the tumor stroma in a PDL1+ patient-derived xenograft model of triple-negative breast cancer. Conclusions These advantages underline the potential of autologous patient-derived NExT to revolutionize tailored adoptive cancer nanotherapy and chemoimmunotherapy, which endorses their widespread clinical application of autologous patient-derived NExT.
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- 2024
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3. Case report: Pilomatrix carcinoma with PDL1 expression and CDKN2A aberrant.
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Abula, Ayinuer, Sheng-Qiang Ma, Sisi Wang, Wei Peng, Xiaming Pei, and Zhe-Yu Hu
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ILIOPSOAS muscle ,GROIN ,CYCLIN-dependent kinase inhibitors ,CARCINOMA ,NUCLEOTIDE sequencing ,GROIN pain - Abstract
Case report: A 55-year-old male patient developed a mass in the left inguinal area with left lower limb swelling and first visited a local hospital 3 months earlier because of unrelieved pain. An MRI scan suggested left suprapubic branch and left acetabular bone destruction, abnormal soft tissue signals within the iliopsoas muscle of the anterior edge of the left iliac bone, and enlarged lymph nodes in the left iliac fossa and left inguinal region. The patient subsequently underwent left pelvic lesion open biopsy and inguinal lymph node resection biopsy. According to pathological reports, the left inguinal mass was considered to be a malignant tumor of cutaneous accessory origin (pilomatrix carcinoma) with extensive vitreous changes. The suprapupubis branch mass was considered to be a bone metastatic pilomatrix carcinoma. Immunohistochemistry (IHC) revealed a PDL1 combined positive score (CPS) of 8. DNA next-generation sequencing (NGS) showed CDKN2A L65Rfs*53 mutation. The patient received three cycles of gemcitabine and nedaplatin. However, the lesion progressed. Conclusion: Chemotherapy is not effective for treating pilomatrix carcinoma. PDL1 antibodies and CDK4/6 inhibitors might be treatment options for pilomatrix carcinoma. [ABSTRACT FROM AUTHOR]
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- 2024
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4. Ketogenic diet enhances the anti-cancer effects of PD-L1 blockade in renal cell carcinoma.
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Richard, Jeremy, Beauvillain, Celine, Benoit, Maxime, Barth, Magalie, Aubert, Cecile, Rolley, Cyrielle, Bellal, Sarah, Bourreau, Jennifer, Ferragu, Matthieu, Lebda, Souhil, Chevrollier, Arnaud, Henrio, Daniel, Procaccio, Vincent, and Bigot, Pierre
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RENAL cell carcinoma ,KETOGENIC diet ,CELL metabolism ,METABOLIC reprogramming ,ANTINEOPLASTIC agents - Abstract
Introduction: Clear cell renal cell carcinoma (ccRCC) is characterized by a predominant metabolic reprogramming triggering energy production by anaerobic glycolysis at the expense of oxydative phosphorylation. Ketogenic diet (KD), which consists of high fat and low carbohydrate intake, could bring required energy substrates to healthy cells while depriving tumor cells of glucose. Our objective was to evaluate the effect of KD on renal cancer cell tumor metabolism and growth proliferation. Methods: Growth cell proliferation and mitochondrial metabolism of ACHN and Renca renal carcinoma cells were evaluated under ketone bodies (KB) exposure. In vivo studies were performed with mice (nude or Balb/c) receiving a xenograft of ACHNcells orRencacells, respectively,andwerethensplit into2feedinggroups, fed either with standard diet or a 2:1 KDad libitum. To test the effect of KDassociated to immunotherapy, Balb/c mice were treated with anti-PDL1 mAb. Tumor growth was monitored. Results: In vitro, KB exposure was associated with a significant reduction of ACHN and Renca cell proliferation and viability, while increasing mitochondrial metabolism. In mice, KD was associated with tumor growth reduction and PDL-1 gene expression up-regulation. In Balb/c mice adjuvant KD was associated to a better response to anti-PDL-1 mAb treatment. Conclusion: KB reduced the renal tumor cell growth proliferation and improved mitochondrial respiration and biogenesis. KD also slowed down tumor growth of ACHNandRenca in vivo.WeobservedthatPDL-1was significantly overexpressed in tumor inmice under KD. Response to anti-PDL-1mAb was improved inmice under KD. Further studies are needed to confirm the therapeutic benefit of adjuvant KD combined with immunotherapy in patients with kidney cancer. [ABSTRACT FROM AUTHOR]
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- 2024
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5. Circular RNA circ_0101675 Promotes NSCLC Cell Proliferation, Migration, Invasion, Angiogenesis and Immune Evasion by Sponging miR-607/PDL1 Axis.
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Lu, Wei, Li, Liang, Li, Li, Guo, Nanbian, and Ma, Ximiao
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CIRCULAR RNA , *PROGRAMMED cell death 1 receptors , *MONONUCLEAR leukocytes , *CELL proliferation , *NON-small-cell lung carcinoma - Abstract
Non-small cell lung cancer (NSCLC) is one of the most common and fatal cancers in the world. Circular RNA (circRNA) can broadly participate in the initiation and progression of the NSCLC. However, the regulatory mechanisms of circRNA in NSCLC remain poorly understood. In present study, we aimed to explore the potential role of circ_0101675 in the progression of NSCLC. Quantitative real-time polymerase chain reaction was performed to examine the expression of circ_0101675, microRNA-607 (miR-607) and programmed cell death receptor ligand 1 (PDL1) in NSCLC tissues and cells. Cell count kit 8 assay, colony formation assay, wound healing assay, transwell assay, tube formation assay and flow cytometry were applied to examine NSCLC cell proliferation, migration, invasion, angiogenesis and apoptosis. NSCLC cells were co-cultured with peripheral blood mononuclear cells to assess immune response. The protein levels of PDL1 and proteins related to apoptosis were detected by western blotting. Dual-luciferase reporter assay and RNA immunoprecipitation assay were conducted to verify the direct target site between miR-607 and circ_0101675 or PDL1. The experiments in vivo were employed to explore the effects of circ_0101675 on tumor growth in NSCLC. Circ_0101675 and PDL1 were high-expressed, while miR-607 was low-expressed in NSCLC cells and cancer tissues. The suppression of circ_0101675 suppressed growth, migration, invasion, angiogenesis and immune escape in NSCLC cells. Mechanistically, we found that high level of circ_0101675 could upregulate PDL1 expression via sponging miR-607. Moreover, the down-regulation of circ_0101675 inhibited the growth of NSCLC tumors in vivo by enhancing miR-607 expression to decrease PDL1 expression. Taken together, our results suggested that circ_0101675 might promote the proliferation, migration, invasion, and immune evasion abilities of NSCLC through miR-607/PDL1 axis. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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6. PD‐L1 regulates tumor proliferation and T‐cell function in NF2‐associated meningiomas.
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Wang, Ying, Zhang, Chao, Yan, Minjun, Ma, Xin, Song, Lairong, Wang, Bo, Li, Peng, and Liu, Pinan
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PROGRAMMED death-ligand 1 , *NEUROFIBROMATOSIS 2 , *T cells , *TUMOR-infiltrating immune cells , *IMMUNOSUPPRESSION , *NEUROFIBROMATOSIS 1 - Abstract
Introduction: Programmed death‐ligand 1 (PD‐L1) expression is an immune evasion mechanism that has been demonstrated in many tumors and is commonly associated with a poor prognosis. Over the years, anti‐PD‐L1 agents have gained attention as novel anticancer therapeutics that induce durable tumor regression in numerous malignancies. They may be a new treatment choice for neurofibromatosis type 2 (NF2) patients. Aims: The aims of this study were to detect the expression of PD‐L1 in NF2‐associated meningiomas, explore the effect of PD‐L1 downregulation on tumor cell characteristics and T‐cell functions, and investigate the possible pathways that regulate PD‐L1 expression to further dissect the possible mechanism of immune suppression in NF2 tumors and to provide new treatment options for NF2 patients. Results: PD‐L1 is heterogeneously expressed in NF2‐associated meningiomas. After PD‐L1 knockdown in NF2‐associated meningioma cells, tumor cell proliferation was significantly inhibited, and the apoptosis rate was elevated. When T cells were cocultured with siPD‐L1‐transfected NF2‐associated meningioma cells, the expression of CD69 on both CD4+ and CD8+ T cells was partly reversed, and the capacity of CD8+ T cells to kill siPD‐L1‐transfected tumor cells was partly restored. Results also showed that the PI3K–AKT–mTOR pathway regulates PD‐L1 expression, and the mTOR inhibitor rapamycin rapidly and persistently suppresses PD‐L1 expression. In vivo experimental results suggested that anti‐PD‐L1 antibody may have a synergetic effect with the mTOR inhibitor in reducing tumor cell proliferation and that reduced PD‐L1 expression could contribute to antitumor efficacy. Conclusions: Targeting PD‐L1 could be helpful for restoring the function of tumor‐infiltrating lymphocytes and inducing apoptosis to inhibit tumor proliferation in NF2‐associated meningiomas. Dissecting the mechanisms of the PD‐L1‐driven tumorigenesis of NF2‐associated meningioma will help to improve our understanding of the mechanisms underlying tumor progression and could facilitate further refinement of current therapies to improve the treatment of NF2 patients. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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7. Circ_0027791 contributes to the growth and immune evasion of hepatocellular carcinoma via the miR‐496/programmed cell death ligand 1 axis in an m6A‐dependent manner.
- Author
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Yu, Furong, Fang, Peifei, Fang, Yonghong, and Chen, Daojun
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CELL death ,HEPATOCELLULAR carcinoma ,MONONUCLEAR leukocytes ,KILLER cells ,CIRCULAR RNA - Abstract
Emerging evidence indicates the critical roles of circular RNAs in the development of multiple cancers, containing hepatocellular carcinoma (HCC). Herein, our present research reported the biological function and mechanism of circ_0027791 in HCC progression. Circ_0027791, microRNA‐496 (miR‐496), programmed cell death ligand 1 (PDL1), and methyltransferase‐like 3 (METTL3) levels were detected by real‐time quantitative polymerase chain reaction (RT‐qPCR). Cell viability, proliferation, invasion, and sphere formation ability were detected using 3‐(4,5‐dimethyl‐2‐thiazolyl)‐2,5‐diphenyl‐2‐H‐tetrazolium bromide, 5‐ethynyl‐2′‐deoxyuridine, transwell, and sphere formation assays. Macrophage polarization was detected using flow cytometry assay. To understand the role of circ_0027791 during the immune escape, HCC cells were cocultured with peripheral blood mononuclear cells or cytokine‐induced killer (CIK) cells in vitro. A xenograft mouse model was applied to assess the function of circ_0027791 in vivo. After prediction using circinteractome and miRDB, the binding between miR‐496 and circ_0027791 or PDL1 was validated based on a dual‐luciferase reporter assay. Interaction between METTL3 and circ_0027791 was determined using methylated RNA immunoprecipitation (MeRIP)‐qPCR, RIP‐qPCR, and RNA pull‐down assays. Circ_0027791, PDL1, and METTL3 expression were upregulated, and miR‐496 was decreased in HCC patients and cells. Moreover, circ_0027791 knockdown might repress proliferation, invasion, sphere formation, M2 macrophage polarization, and antitumor immune response. Circ_0027791 knockdown repressed HCC tumor growth in vivo. In mechanism, circ_0027791 functioned as a sponge for miR‐496 to increase PDL1 expression. In addition, METTL3 mediated the m6A methylation of circ_0027791 and stabilized its expression. METTL3‐induced circ_0027791 facilitated HCC cell progression partly regulating the miR‐496/PDL1 axis, which provided a new prognostic and therapeutic marker for HCC. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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8. Autologous patient-derived exhausted nano T-cells exploit tumor immune evasion to engage an effective cancer therapy.
- Author
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Blaya-Cánovas, José L., Griñán-Lisón, Carmen, Blancas, Isabel, Marchal, Juan A., Ramírez-Tortosa, César, López-Tejada, Araceli, Benabdellah, Karim, Cortijo-Gutiérrez, Marina, Cano-Cortés, M. Victoria, Graván, Pablo, Navarro-Marchal, Saúl A., Gómez-Morales, Jaime, Delgado-Almenta, Violeta, Calahorra, Jesús, Agudo-Lera, María, Sagarzazu, Amaia, Rodríguez-González, Carlos J., Gallart-Aragón, Tania, Eich, Christina, and Sánchez-Martín, Rosario M.
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T-cell exhaustion , *CANCER treatment , *DRUG delivery systems , *TRIPLE-negative breast cancer , *IMMUNE checkpoint proteins - Abstract
Background: Active targeting by surface-modified nanoplatforms enables a more precise and elevated accumulation of nanoparticles within the tumor, thereby enhancing drug delivery and efficacy for a successful cancer treatment. However, surface functionalization involves complex procedures that increase costs and timelines, presenting challenges for clinical implementation. Biomimetic nanoparticles (BNPs) have emerged as unique drug delivery platforms that overcome the limitations of actively targeted nanoparticles. Nevertheless, BNPs coated with unmodified cells show reduced functionalities such as specific tumor targeting, decreasing the therapeutic efficacy. Those challenges can be overcome by engineering non-patient-derived cells for BNP coating, but these are complex and cost-effective approaches that hinder their wider clinical application. Here we present an immune-driven strategy to improve nanotherapeutic delivery to tumors. Our unique perspective harnesses T-cell exhaustion and tumor immune evasion to develop a groundbreaking new class of BNPs crafted from exhausted T-cells (NExT) of triple-negative breast cancer (TNBC) patients by specific culture methods without sophisticated engineering. Methods: NExT were generated by coating PLGA (poly(lactic-co-glycolic acid)) nanoparticles with TNBC-derived T-cells exhausted in vitro by acute activation. Physicochemical characterization of NExT was made by dynamic light scattering, electrophoretic light scattering and transmission electron microscopy, and preservation and orientation of immune checkpoint receptors by flow cytometry. The efficacy of chemotherapy-loaded NExT was assessed in TNBC cell lines in vitro. In vivo toxicity was made in CD1 mice. Biodistribution and therapeutic activity of NExT were determined in cell-line- and autologous patient-derived xenografts in immunodeficient mice. Results: We report a cost-effective approach with a good performance that provides NExT naturally endowed with immune checkpoint receptors (PD1, LAG3, TIM3), augmenting specific tumor targeting by engaging cognate ligands, enhancing the therapeutic efficacy of chemotherapy, and disrupting the PD1/PDL1 axis in an immunotherapy-like way. Autologous patient-derived NExT revealed exceptional intratumor accumulation, heightened chemotherapeutic index and efficiency, and targeted the tumor stroma in a PDL1+ patient-derived xenograft model of triple-negative breast cancer. Conclusions: These advantages underline the potential of autologous patient-derived NExT to revolutionize tailored adoptive cancer nanotherapy and chemoimmunotherapy, which endorses their widespread clinical application of autologous patient-derived NExT. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
9. Prognostic Value of KRAS Mutations in Relation to PDL1 Expression and Immunotherapy Treatment in Adenocarcinoma and Squamous Cell Carcinoma Patients: A Greek Cohort Study.
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Tsiouda, Theodora, Domvri, Kalliopi, Boutsikou, Efimia, Bikos, Vasileios, Kyrka, Krystallia, Papadaki, Konstantina, Pezirkianidou, Persefoni, Porpodis, Konstantinos, and Cheva, Angeliki
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GENE expression , *SQUAMOUS cell carcinoma , *RAS oncogenes , *PROGNOSIS , *NON-small-cell lung carcinoma - Abstract
Background: Factors that could predict which patients will benefit from Immune Checkpoint Inhibitors (ICIs) are not fully understood. This study aimed to investigate the prognostic value of KRAS biomarker in patients with advanced non-small cell lung cancer (NSCLC) in relation to clinical characteristics, treatment response and PDL1 expression. Patients and methods: The study included 100 patients with NSCLC who received immunotherapy with or without chemotherapy as 1st line treatment. In biopsy samples, the PDL1 biomarker expression rate and somatic mutations of KRAS gene were determined. Results: The mean age of the patients was 67 ± 8 years. Patients were all male and 66% were found with adenocarcinoma whereas 34% with squamous cell carcinoma. The KRAS G12C mutation was found with the highest percentage (73%). In the Kaplan-Meier survival analysis, patients with PDL1 > 49% in combination with a negative KRAS result had a median overall survival of 40 months compared to patients with a positive KRAS result (9 months, p < 0.05). In addition, patients diagnosed with adenocarcinoma, PDL1 < 49% and negative KRAS result had a median overall survival of 39 months compared to patients with a positive result (28 months, p < 0.05). Conclusions: Our study suggests that the presence of KRAS mutations in advanced NSCLC patients has a poor prognostic value, regardless of their PDL1 expression values, after receiving immunotherapy as first-line treatment. [ABSTRACT FROM AUTHOR]
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- 2024
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10. A TFEB -Amplified Renal Cell Carcinoma with Long-Term, Complete Immunotherapy Response: Retrospective Support for the Value of Molecular Classification.
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Smith, Steven Christopher, Yu, Jinxing, and Paul, Asit K
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RENAL cell carcinoma , *IMMUNOTHERAPY , *KIDNEY tumors , *SCHOLARLY method , *CLASSIFICATION - Abstract
Recent years have seen the recognition and establishment of numerous subtypes of renal cell carcinoma (RCC), including adoption of an entire category of "molecularly defined renal carcinomas" in the fifth Edition of World Health Organization Classification. To add value, new diagnostic entities should be clinicopathologically distinct, or better, imply specific management and treatment angles, especially if adjunctive testing is needed for diagnosis. One such promising future treatment angle for a molecularly defined subtype, TFEB -amplified RCC, is immunotherapy, for which recent scholarship has demonstrated frequent expression of PD-L1. Herein, we report a case of metastatic TFEB -amplified RCC, where the patient experienced a long-term, complete response to PDL1-directed therapy, which had been serendipitously used years ago under a renal tumor subtype-agnostic indication. This promising experience suggests formal exploration of immunotherapy for these tumors. [ABSTRACT FROM AUTHOR]
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- 2024
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11. Evaluation of PDL1 positive cancer cell‐specific binding activity of recombinant anti‐PDL1 scFv.
- Author
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Kim, Sun‐Hee, Park, Hae‐Min, and Jeong, Hee‐Jin
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ENZYME-linked immunosorbent assay ,PROGRAMMED death-ligand 1 ,IMMUNOASSAY ,MEMBRANE proteins ,WESTERN immunoblotting ,RECOMBINANT proteins ,CANCER cells - Abstract
Programmed cell death‐ligand 1 (PDL1) is a transmembrane protein that is characterized as an immune regulatory molecule. We recently developed a recombinant single‐chain fragment of variable domain (scFv) against PDL1, which showed high binding efficiency to purified recombinant PDL1 protein. However, at that time, proof‐of‐concept data for the effect of scFv using PDL1‐expressing cells was lacking. In this study, we conducted two kinds of cell‐based immunoassays, western blotting and enzyme‐linked immunosorbent assay, using anti‐PDL1 scFv. The results indicate that scFv can selectively and sensitively detect PDL1 from PDL1 positive human cancer cell lines. Our findings suggest that scFv could be used as a potential PDL1 inhibitor agent and probe for cell‐based immunoassays to detect PDL1. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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12. lncRNA MIAT promotes luminal B breast cancer cell proliferation, migration, and invasion in vitro.
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Mi, Jintao, Zhang, Hongsheng, Jiang, Xuemei, Yi, Ying, Cao, Weiwei, Song, Chunjiao, and Yuan, Chengliang
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Long noncoding RNAs (lncRNAs) play a role in the emergence and progression of several human tumors, including luminal B breast cancer (BC). The biological functions and potential mechanisms of lncRNA myocardial infarction-associated transcripts (MIAT) in luminal B BC, on the contrary, are unknown. In this work, we used UALCAN database analysis to find high expression of lncRNA MIAT in luminal BC tissues and also confirmed high levels of lncRNA MIAT expression in luminal B BC tissues and cells. In vitro knockdown of MIAT inhibited the proliferation, migration, and invasion of BT474 cells. In addition, we found that miR-150-5p levels were significantly reduced in luminal B BC specimens and cells, and miR-150-5p levels were significantly increased when MIAT was knocked down. And TIMER database analysis showed that MIAT was positively associated with PDL1. Through bioinformatic tools and in vitro experiments, lncRNA MIAT could function as a competitive endogenous RNA (CeRNA) to further regulate programmed cell death ligand 1 (PDL1) expression by directly sponging miR-150-5p. In conclusion, our data suggest that MIAT, an oncogene, may sponge miR-150-5p to regulate PDL1 expression and affect proliferation, migration, and invasion in luminal B BC in vitro. [ABSTRACT FROM AUTHOR]
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- 2024
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13. PDL1 immunohistochemistry in canine neoplasms: Validation of commercial antibodies, standardization of evaluation, and scoring systems.
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Muscatello, Luisa Vera, Gobbo, Francesca, Avallone, Giancarlo, Innao, Micaela, Benazzi, Cinzia, D'Annunzio, Giulia, Romaniello, Donatella, Orioles, Massimo, Lauriola, Mattia, and Sarli, Giuseppe
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IMMUNE checkpoint proteins ,RENAL cell carcinoma ,TUMOR-infiltrating immune cells ,IMMUNOGLOBULINS ,IMMUNOHISTOCHEMISTRY - Abstract
Immuno-oncology research has brought to light the paradoxical role of immune cells in the induction and elimination of cancer. Programmed cell death protein 1 (PD1), expressed by tumor-infiltrating lymphocytes, and programmed cell death ligand 1 (PDL1), expressed by tumor cells, are immune checkpoint proteins that regulate the antitumor adaptive immune response. This study aimed to validate commercially available PDL1 antibodies in canine tissue and then, applying standardized methods and scoring systems used in human pathology, evaluate PDL1 immunopositivity in different types of canine tumors. To demonstrate cross-reactivity, a monoclonal antibody (22C3) and polyclonal antibody (cod. A1645) were tested by western blot. Cross-reactivity in canine tissue cell extracts was observed for both antibodies; however, the polyclonal antibody (cod. A1645) demonstrated higher signal specificity. Canine tumor histotypes were selected based on the human counterparts known to express PDL1. Immunohistochemistry was performed on 168 tumors with the polyclonal anti-PDL1 antibody. Only membranous labeling was considered positive. PDL1 labeling was detected both in neoplastic and infiltrating immune cells. The following tumors were immunopositive: melanomas (17 of 17; 100%), renal cell carcinomas (4 of 17; 24%), squamous cell carcinomas (3 of 17; 18%), lymphomas (2 of 14; 14%), urothelial carcinomas (2 of 18; 11%), pulmonary carcinomas (2 of 20; 10%), and mammary carcinomas (1 of 31; 3%). Gastric (0 of 10; 0%) and intestinal carcinomas (0 of 24; 0%) were negative. The findings of this study suggest that PDL1 is expressed in some canine tumors, with high prevalence in melanomas. [ABSTRACT FROM AUTHOR]
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- 2024
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14. VISTA/CTLA4/PD1 coexpression on tumor cells confers a favorable immune microenvironment and better prognosis in high-grade serous ovarian carcinoma.
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Jlassi, Aida, Rejaibi, Rim, Manai, Maroua, Sahraoui, Ghada, Guerfali, Fatma Zahra, Charfi, Lamia, Mezlini, Amel, Manai, Mohamed, Mrad, Karima, and Doghri, Raoudha
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REGULATORY T cells ,GENE expression ,IMMUNE checkpoint proteins ,PROGNOSIS ,CARCINOMA - Abstract
Introduction: Immunotherapy by blocking immune checkpoints programmed death/ligand (PD1/PDL1) and cytotoxic T-lymphocyte-associated protein 4(CTLA4) has emerged as new therapeutic targets in cancer. However, their efficacy has been limited due to resistance. A new- checkpoint V-domain Ig-containing suppressor of T cell activation (VISTA) has appeared, but the use of its inhibition effect in combination with antibodies targeting PDL1/PD1and CTLA4 has not been reported in ovarian cancer. Methods: In this study, we investigated the expressions of VISTA, CTLA4, and PDL1 using immunohistochemistry (IHC)on 135 Formalin-Fixed Paraffin-Embedded (FFPE)tissue samples of High-grade serous carcinoma (HGSOC). VISTA, CTLA4, PDL1, PD1, CD8, CD4, and FOXP3 mRNA extracted from 429 patients with ovarian cancer in the Cancer Genome Atlas (TCGA) database was included as a validation cohort. Correlations between these checkpoints, tumor-infiltrating- lymphocytes (TILs), and survival were analyzed. Results and discussion: CTLA4 was detectable in 87.3% of samples, VISTA in 64.7%, PD1 in 56.7%, and PDL1 in 48.1%. PDL1 was the only tested protein associated with an advanced stage (p=0.05). VISTA was associated with PDL1, PD1, and CTLA4 expressions (p=0.005, p=0.001, p=0.008, respectively), consistent with mRNA level analysis from the TCGA database. Univariate analyses showed only VISTA expression (p=0.04) correlated with overall survival (OS). Multivariate analyses showed that VISTA expression (p=0.01) and the coexpression of VISTA
+ /CTLA4+ /PD1+ (p=0.05) were associated with better OS independently of the clinicopathological features. Kaplan-Meier analysis showed that the coexpression of the VISTA+ /CTLA4+ /PDL1+ and VISTA+/CTLA4+/PD1+ checkpoints on tumor cells (TCs)were associated with OS (p=0.02 and p<0.001; respectively). VISTA+ /CTLA4+ /PD1+ in TCs and CD4+ /CD8+ TILs were associated with better 2-yer OS. This correlation may refer to the role of VISTA as a receptor in the TCs and not in the immune cells. Thus, targeting combination therapy blocking VISTA, CTLA4, and PD1 could be a novel and attractive strategy for HGSOC treatment, considering the ambivalent role of VISTA in the HGSOC tumor cells. [ABSTRACT FROM AUTHOR]- Published
- 2024
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15. Intracranial Efficacy of Atezolizumab, Bevacizumab, Carboplatin, and Paclitaxel in Real-World Patients with Non-Small-Cell Lung Cancer and EGFR or ALK Alterations.
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Rathbone, Marcus, O'Hagan, Conor, Wong, Helen, Khan, Adeel, Cook, Timothy, Rose, Sarah, Heseltine, Jonathan, and Escriu, Carles
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BRAIN physiology , *THERAPEUTIC use of monoclonal antibodies , *BEVACIZUMAB , *ANTINEOPLASTIC agents , *IMMUNOTHERAPY , *PROTEIN-tyrosine kinase inhibitors , *SMOKING , *CARBOPLATIN , *CANCER patients , *TREATMENT effectiveness , *RETROSPECTIVE studies , *DESCRIPTIVE statistics , *LONGITUDINAL method , *LUNG tumors , *ANAPLASTIC lymphoma kinase , *DRUG efficacy , *LUNG cancer , *PACLITAXEL , *GENETIC mutation , *PROGRESSION-free survival , *EPIDERMAL growth factor receptors , *OVERALL survival , *BRAIN tumors , *EVALUATION - Abstract
Simple Summary: Patients with oncogene-addicted lung cancers that have developed resistance to oral targeted therapy have limited treatment options. Several studies have shown conflicting results in this setting, but those using Bevacizumab and Paclitaxel in combination with immunotherapy (ABCP) have consistently shown activity. Spread to the brain is common, but it is not known how many patients with brain metastases are amenable to chemo-immunotherapy, and its effect in this patient group has not been reported to date. We present here our retrospective real-life experience in patients treated with ABCP. Our results in 34 patients underlined that spread to the brain occurred in 19 patients (56%), 17 of them without previous brain radiotherapy. In these 19 patients, chemo-immunotherapy triggered frequent and quick responses inside and outside the brain and showed similar outcomes to those shown in patients with smoking-related lung cancer and previously untreated brain metastases. Contrary to Pemetrexed-containing chemo-immunotherapy studies, Atezolizumab, Bevacizumab, Carboplatin, and Paclitaxel (ABCP) treatment has consistently shown clinical benefit in prospective studies in patients with lung cancer and actionable mutations, where intracranial metastases are common. Here, we aimed to describe the real-life population of patients fit to receive ABCP after targeted therapy and quantify its clinical effect in patients with brain metastases. Patients treated in Cheshire and Merseyside between 2019 and 2022 were identified. Data were collected retrospectively. A total of 34 patients with actionable EGFR or ALK alterations had treatment with a median age of 59 years (range 32–77). The disease control rate was 100% in patients with PDL1 ≥ 1% (n = 10). In total, 19 patients (56%) had brain metastases before starting ABCP, 17 (50%) had untreated CNS disease, and 4 (22%) had PDL1 ≥ 1%. The median time to symptom improvement was 12.5 days (range 4–21 days), with 74% intracranial disease control rates and 89.5% synchronous intracranial (IC) and extracranial (EC) responses. IC median Progression Free Survival (mPFS) was 6.48 months, EC mPFS was 10.75 months, and median Overall Survival 11.47 months. ABCP in real-life patients with brain metastases (treated or untreated) was feasible and showed similar efficacy to that described in patients without actionable mutations treated with upfront chemo-immunotherapy. [ABSTRACT FROM AUTHOR]
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- 2024
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16. Cholesterol suppresses AMFR-mediated PDL1 ubiquitination and degradation in HCC
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Shao, Wei-Qing, Li, Yi-Tong, Zhou, Xu, Zhang, Sheng-Guo, Fan, Ming-Hao, Zhang, Dong, Chen, Zhen-Mei, Yi, Chen-He, Wang, Sheng-Hao, Zhu, Wen-Wei, Lu, Ming, Chen, Ji-Song, Lin, Jing, and Zhou, Yu
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- 2024
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17. Response to immune checkpoint inhibitor combination therapy in metastatic RET-mutated lung cancer from real-world retrospective data
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Ningning Yan, Huixian Zhang, Shujing Shen, Sanxing Guo, and Xingya Li
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RET ,Non-small cell lung cancer ,PDL1 ,TMB ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background The impact of immune checkpoint inhibitors (ICIs) based treatments on non-small cell lung cancers (NSCLCs) with RET fusions remains poorly understood. Methods We screened patients with RET fusions at the First Affiliated Hospital of Zhengzhou University and included those who were treated with ICIs based regimens for further analysis. We evaluated clinical indicators including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Results A total of 232 patients with RET fusions were included in the study. Of these, 129 patients had their programmed death-ligand 1 (PDL1) expression levels tested, with 22 patients (17.8%) having a PDL1 level greater than or equal to 50%. Additionally, tumor mutational burden (TMB) status was evaluated in 35 patients, with the majority (30/35, 85.8%) having a TMB of less than 10 mutations per megabase. Out of the 38 patients treated with ICI based regimens, the median PFS was 5 months (95% confidence interval [CI]: 2.4–7.6 months) and the median OS was 19 months (95% CI: 9.7–28.3 months) at the time of data analysis. Stratification based on treatment lines did not show any significant differences in OS (18 vs. 19 months, p = 0.63) and PFS (6 vs. 5 months, p = 0.86). The ORR for patients treated with ICIs was 26.3%. Furthermore, no significant differences were found for PFS (p = 0.27) and OS (p = 0.75) between patients with positive and negative PDL1 expression. Additionally, there was no significant difference in PD-L1 levels (p = 0.10) between patients who achieved objective response and those who did not. Conclusions Patients with RET fusion positive NSCLCs may not benefit from ICI based regimens and therefore should not be treated with ICIs in clinical practice.
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- 2024
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18. Development of a Bispecific IgG1 Antibody Targeting BCMA and PDL1.
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Cattaneo, Irene, Choblet, Sylvie, Valgardsdottir, Rut, Roth, Muriel, Massafra, Annamaria, Beeg, Marten, Gobbi, Marco, Duonor-Cerutti, Martine, and Golay, Josée
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BISPECIFIC antibodies , *MONONUCLEAR leukocytes , *SURFACE plasmon resonance , *KILLER cells , *IMMUNE checkpoint inhibitors , *BORTEZOMIB - Abstract
We designed, produced, and purified a novel IgG1-like, bispecific antibody (bsAb) directed against B-cell maturation antigen (BCMA), expressed by multiple myeloma (MM) cells, and an immune checkpoint inhibitor (ICI), PDL1, expressed in the MM microenvironment. The BCMA×PDL1 bsAb was fully characterized in vitro. BCMA×PDL1 bound specifically and simultaneously, with nM affinity, to both native membrane-bound antigens and to the recombinant soluble antigen fragments, as shown by immunophenotyping analyses and surface plasmon resonance (SPR), respectively. The binding affinity of bsAb for PDL1 and BCMA was similar to each other, but PDL1 affinity was about 10-fold lower in the bsAb compared to parent mAb, probably due to the steric hindrance associated with the more internal anti-PDL1 Fab. The bsAb was also able to functionally block both antigen targets with IC50 in the nM range. The bsAb Fc was functional, inducing human-complement-dependent cytotoxicity as well as ADCC by NK cells in 24 h killing assays. Finally, BCMA×PDL1 was effective in 7-day killing assays with peripheral blood mononuclear cells as effectors, inducing up to 75% of target MM cell line killing at a physiologically attainable, 6 nM, concentration. These data provide the necessary basis for future optimization and in vivo testing of this novel bsAb. [ABSTRACT FROM AUTHOR]
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- 2024
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19. EVALUACIÓN DE LA EXPRESIÓN DE PD-L1 E INFILTRACIÓN LINFOCITARIA INTRATUMORAL EN CARCINOMA DE MAMA INVASIVO TRIPLE NEGATIVO.
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BARRIOS BARRETO, RINA, SILVERA REDONDO, CARLOS, GARAVITO, MARÍA DEL PILAR, and ARDILA PEREIRA, LAURA
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- 2024
20. Platinum-based neoadjuvant chemotherapy upregulates STING/IFN pathway expression and promotes TILs infiltration in NSCLC.
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Huan Gao, Xiaoni Zhang, Mengdi Ren, Aimin Jiang, Na Liu, Jingjing Wang, Xiaoqiang Zheng, Xuan Liang, Zhiping Ruan, Tao Tian, Xiao Fu, and Yu Yao
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NEOADJUVANT chemotherapy ,OVARIAN epithelial cancer ,NON-small-cell lung carcinoma ,COMBINATION drug therapy ,PROGNOSIS - Abstract
Objectives: To evaluate the effects of platinum-based neoadjuvant chemotherapy (NACT) on the STING/IFN pathway and tumor-infiltrating lymphocytes (TILs) in non-small cell lung cancer (NSCLC), as well as clinicopathological factors affecting patient survival. Materials and methods: A total of 68 patients aged 34-77 years with NSCLC who received neoadjuvant chemotherapy and surgical treatment from March 2012 to February 2019 were reviewed, and the clinical pathological data and paired tissue specimens before and after NACT were collected. Immunohistochemistry and immunofluorescence were used to detect the protein levels of STING, PD-L1 and IFN-b, and the infiltration density of CD3
+ TILs and CD8+ TILs. The correlation between the expression of STING, PD-L1, IFN-b and the infiltration density of CD3+ TILs and CD8+ TILs as well as the clinicopathological characteristics before and after NACT was analyzed. The relationship between the related indexes, clinicopathological features and prognosis was also discussed. Results: NACT increased the expression of STING, IFN-β and PD-L1 in tumor cells, and the infiltration of CD3+ and CD8+ TILs. In addition, ypTNM stage, ypN stage, changes in CD3+ TILs and in PD-L1 were associated with DFS (disease-free survival). CD3+ TILs changes and ypN stage were associated with OS (overall survival). Notably, ypN stage and CD3+ TILs changes were independent prognostic factors for DFS and OS. Conclusion: NACT stimulates STING/IFN-β pathway, promotes infiltration of CD3+ and CD8+ TILs, triggers innate and adaptive immunity, and also upregulates PD-L1, which complemented the rationale for neoadjuvant chemotherapy in combination with immunotherapy. In addition, DFS was longer in patients with ypTNM I, ypN0-1, and elevated CD3+ TILs after NACT. Patients with ypN0 and elevated CD3+ TILs after NACT had better OS benefits. [ABSTRACT FROM AUTHOR]- Published
- 2024
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21. Response to immune checkpoint inhibitor combination therapy in metastatic RET-mutated lung cancer from real-world retrospective data.
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Yan, Ningning, Zhang, Huixian, Shen, Shujing, Guo, Sanxing, and Li, Xingya
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IMMUNE checkpoint inhibitors , *PROGRAMMED death-ligand 1 , *NON-small-cell lung carcinoma , *LUNG cancer , *IPILIMUMAB , *IMMUNE response - Abstract
Background: The impact of immune checkpoint inhibitors (ICIs) based treatments on non-small cell lung cancers (NSCLCs) with RET fusions remains poorly understood. Methods: We screened patients with RET fusions at the First Affiliated Hospital of Zhengzhou University and included those who were treated with ICIs based regimens for further analysis. We evaluated clinical indicators including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Results: A total of 232 patients with RET fusions were included in the study. Of these, 129 patients had their programmed death-ligand 1 (PDL1) expression levels tested, with 22 patients (17.8%) having a PDL1 level greater than or equal to 50%. Additionally, tumor mutational burden (TMB) status was evaluated in 35 patients, with the majority (30/35, 85.8%) having a TMB of less than 10 mutations per megabase. Out of the 38 patients treated with ICI based regimens, the median PFS was 5 months (95% confidence interval [CI]: 2.4–7.6 months) and the median OS was 19 months (95% CI: 9.7–28.3 months) at the time of data analysis. Stratification based on treatment lines did not show any significant differences in OS (18 vs. 19 months, p = 0.63) and PFS (6 vs. 5 months, p = 0.86). The ORR for patients treated with ICIs was 26.3%. Furthermore, no significant differences were found for PFS (p = 0.27) and OS (p = 0.75) between patients with positive and negative PDL1 expression. Additionally, there was no significant difference in PD-L1 levels (p = 0.10) between patients who achieved objective response and those who did not. Conclusions: Patients with RET fusion positive NSCLCs may not benefit from ICI based regimens and therefore should not be treated with ICIs in clinical practice. [ABSTRACT FROM AUTHOR]
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- 2024
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22. Reprogramming tumor-associated macrophages by a dually targeted milk exosome system as a potent monotherapy for cancer.
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Chen, Ying, Gong, Liang, Cao, Yulin, Liu, Zhiang, Wang, Yuanben, Cheng, Han, Feng, Yuyang, Yao, Surui, Yin, Yuan, Wu, Zhimeng, and Huang, Zhaohui
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NANOMEDICINE , *EPIDERMAL growth factor receptors , *EXOSOMES , *MACROPHAGES , *T cells , *IMMUNE checkpoint proteins , *PEPTIDES - Abstract
Tumor-associated macrophages (TAMs) play a key role in inducing an immunosuppressive tumor microenvironment (TME) and cancer immune escape. We previously revealed that PDL1 (a key immune checkpoint) was upregulated in TAMs and induced M2 polarization, highlighting PDL1 in TAMs as a promising cancer therapeutic target. In this study, we developed an engineered milk exosome (mExo) system decorated with M2pep (an M2 macrophage binding peptide) and 7D12 (an anti-EGFR nanobody) (7D12-mExo-M2pep-siPDL1) to specifically deliver siPDL1 into M2 TAMs. A series of in vitro and in vivo assays showed that the dually targeted engineered mExos efficiently delivered siPDL1 into M2 TAMs and repolarized them into M1 macrophages, restoring CD8+ T cell immune activity and remodeling TME. Importantly, systemically administered 7D12-mExo-M2pep-siPDL1 showed efficient single-agent antitumor activity, resulting in nearly 90% tumor growth inhibition in a mouse model of orthotopic epidermal growth factor receptor (EGFR) cancer. Collectively, our study indicates that PDL1 is a promising target for TAM-based cancer immunotherapy, and our engineered mExo-based nanomedicine represents a novel tool for specifically targeting M2 TAMs, distinguishing this novel therapeutic method from other TAM-targeting therapies and highlighting its promising clinical potential. [Display omitted] • An engineered mExo system decorated with M2pep and EGFR nanobody was developed. • PDL1 is a promising target for TAM-based cancer immunotherapy. • The engineered mExo system specifically deliver siPDL1 into M2 TAMs. • The engineered mExo system showed efficient antitumor activity for EGFR+ tumors. [ABSTRACT FROM AUTHOR]
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- 2024
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23. Immune Escape Strategies in Head and Neck Cancer: Evade, Resist, Inhibit, Recruit.
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Kostecki, Kourtney L., Iida, Mari, Crossman, Bridget E., Salgia, Ravi, Harari, Paul M., Bruce, Justine Y., and Wheeler, Deric L.
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DISEASE progression , *STRATEGIC planning , *HEAD & neck cancer , *IMMUNOTHERAPY - Abstract
Simple Summary: Head and neck cancer (HNC) is an aggressive form of cancer that affects hundreds of thousands of people worldwide and has a relatively poor prognosis. In the last decade, new therapeutics designed to enhance a patient's immune system have been approved for use, but HNC has developed many different methods that help it escape the immune system. The existing immunotherapies target only one of these mechanisms, allowing HNC to utilize others to continue to elude the immune system. This review details the various strategies used by HNC to escape the immune response, dividing them into four general categories: evade, resist, inhibit, and recruit. Each of the immune escape mechanisms represents a potential immunotherapy target that could be used to treat HNC. Head and neck cancers (HNCs) arise from the mucosal lining of the aerodigestive tract and are often associated with alcohol use, tobacco use, and/or human papillomavirus (HPV) infection. Over 600,000 new cases of HNC are diagnosed each year, making it the sixth most common cancer worldwide. Historically, treatments have included surgery, radiation, and chemotherapy, and while these treatments are still the backbone of current therapy, several immunotherapies have recently been approved by the Food and Drug Administration (FDA) for use in HNC. The role of the immune system in tumorigenesis and cancer progression has been explored since the early 20th century, eventually coalescing into the current three-phase model of cancer immunoediting. During each of the three phases—elimination, equilibrium, and escape—cancer cells develop and utilize multiple strategies to either reach or remain in the final phase, escape, at which point the tumor is able to grow and metastasize with little to no detrimental interference from the immune system. In this review, we summarize the many strategies used by HNC to escape the immune system, which include ways to evade immune detection, resist immune cell attacks, inhibit immune cell functions, and recruit pro-tumor immune cells. [ABSTRACT FROM AUTHOR]
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- 2024
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24. PD-L1 and PD-1 Expression in Early Stage Uterine Endometrioid Carcinoma.
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HYO JUNG AN, JUNG WOOK YANG, MIN HYE KIM, and DAE HYUN SONG
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PROTEIN expression ,ENDOMETRIAL cancer ,PROGRAMMED cell death 1 receptors ,IMMUNE checkpoint inhibitors ,TUMOR-infiltrating immune cells - Abstract
Background/Aim: Immune checkpoint inhibitors (ICI) and tumor-infiltrating lymphocytes (TILs) for cancer treatment in clinical oncology have revolutionized patient care. However, no gold standard exists for the criteria of analytical validity of TILs of different types of cancer. Materials and Methods: Clinicopathological data from 60 patients with endometrioid carcinoma (EC) who had undergone surgical treatment at the Gyeongsang National University Hospital between January 2002 and December 2009, were investigated. The programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PDL1) expression levels were characterized by immunohistochemical staining patterns, and the interpretations derived from machine learning morphometric analysis (Genie) and the pathologists' assessments were compared. In solid tumors, pathologists assessed the proportion of positive cells in each core of the tissue microarray. For Genie, the proportion of positive cells in the entire core and the number of positive cells per 1 mm² were used. Results: Both the pathologists and Genie identified the same trend in association with tumor size, with significant differences (p=0.026, p=0.033). Genie expression showed a significant association with PD1 expression, and pathologists identified a significant association with PDL1 expression in immune cells. Conclusion: The PD1 expression levels identified in immune cells of EC specimens were similar between the pathologists and Genie, suggesting that there is little resistance to the introduction of morphometric analysis. To our knowledge, this is the first study to introduce and validate machine learning as an integrated method for predicting prognosis and treatment based on PD1 expression in EC tumor microenvironments. [ABSTRACT FROM AUTHOR]
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- 2024
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25. Case report: Pilomatrix carcinoma with PDL1 expression and CDKN2A aberrant
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Ayinuer Abula, Sheng-Qiang Ma, Sisi Wang, Wei Peng, Xiaming Pei, and Zhe-Yu Hu
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pilomatrix carcinoma ,PDL1 ,PD1 ,CDKN2A ,chemotherapy ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Case reportA 55-year-old male patient developed a mass in the left inguinal area with left lower limb swelling and first visited a local hospital 3 months earlier because of unrelieved pain. An MRI scan suggested left suprapubic branch and left acetabular bone destruction, abnormal soft tissue signals within the iliopsoas muscle of the anterior edge of the left iliac bone, and enlarged lymph nodes in the left iliac fossa and left inguinal region. The patient subsequently underwent left pelvic lesion open biopsy and inguinal lymph node resection biopsy. According to pathological reports, the left inguinal mass was considered to be a malignant tumor of cutaneous accessory origin (pilomatrix carcinoma) with extensive vitreous changes. The suprapupubis branch mass was considered to be a bone metastatic pilomatrix carcinoma. Immunohistochemistry (IHC) revealed a PDL1 combined positive score (CPS) of 8. DNA next-generation sequencing (NGS) showed CDKN2A L65Rfs*53 mutation. The patient received three cycles of gemcitabine and nedaplatin. However, the lesion progressed.ConclusionChemotherapy is not effective for treating pilomatrix carcinoma. PDL1 antibodies and CDK4/6 inhibitors might be treatment options for pilomatrix carcinoma.
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- 2024
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26. Ketogenic diet enhances the anti-cancer effects of PD-L1 blockade in renal cell carcinoma
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Jeremy Richard, Céline Beauvillain, Maxime Benoit, Magalie Barth, Cécile Aubert, Cyrielle Rolley, Sarah Bellal, Jennifer Bourreau, Matthieu Ferragu, Souhil Lebdai, Arnaud Chevrollier, Daniel Henrion, Vincent Procaccio, and Pierre Bigot
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renal cell carcinoma ,metabolic reprogramming ,mitochondrial biogenesis ,PDL1 ,adjuvant ketogenic diet ,immunotherapy ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
IntroductionClear cell renal cell carcinoma (ccRCC) is characterized by a predominant metabolic reprogramming triggering energy production by anaerobic glycolysis at the expense of oxydative phosphorylation. Ketogenic diet (KD), which consists of high fat and low carbohydrate intake, could bring required energy substrates to healthy cells while depriving tumor cells of glucose. Our objective was to evaluate the effect of KD on renal cancer cell tumor metabolism and growth proliferation.MethodsGrowth cell proliferation and mitochondrial metabolism of ACHN and Renca renal carcinoma cells were evaluated under ketone bodies (KB) exposure. In vivo studies were performed with mice (nude or Balb/c) receiving a xenograft of ACHN cells or Renca cells, respectively, and were then split into 2 feeding groups, fed either with standard diet or a 2:1 KD ad libitum. To test the effect of KD associated to immunotherapy, Balb/c mice were treated with anti-PDL1 mAb. Tumor growth was monitored.ResultsIn vitro, KB exposure was associated with a significant reduction of ACHN and Renca cell proliferation and viability, while increasing mitochondrial metabolism. In mice, KD was associated with tumor growth reduction and PDL-1 gene expression up-regulation. In Balb/c mice adjuvant KD was associated to a better response to anti-PDL-1 mAb treatment.ConclusionKB reduced the renal tumor cell growth proliferation and improved mitochondrial respiration and biogenesis. KD also slowed down tumor growth of ACHN and Renca in vivo. We observed that PDL-1 was significantly overexpressed in tumor in mice under KD. Response to anti-PDL-1 mAb was improved in mice under KD. Further studies are needed to confirm the therapeutic benefit of adjuvant KD combined with immunotherapy in patients with kidney cancer.
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- 2024
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27. VISTA/CTLA4/PD1 coexpression on tumor cells confers a favorable immune microenvironment and better prognosis in high-grade serous ovarian carcinoma
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Aida Jlassi, Rim Rejaibi, Maroua Manai, Ghada Sahraoui, Fatma Zahra Guerfali, Lamia Charfi, Amel Mezlini, Mohamed Manai, Karima Mrad, and Raoudha Doghri
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ovarian cancer ,HGSOC ,VISTA ,CTLA4 ,PDL1 ,PD1 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
IntroductionImmunotherapy by blocking immune checkpoints programmed death/ligand (PD1/PDL1) and cytotoxic T-lymphocyte-associated protein 4(CTLA4) has emerged as new therapeutic targets in cancer. However, their efficacy has been limited due to resistance. A new- checkpoint V-domain Ig-containing suppressor of T cell activation (VISTA) has appeared, but the use of its inhibition effect in combination with antibodies targeting PDL1/PD1and CTLA4 has not been reported in ovarian cancer.MethodsIn this study, we investigated the expressions of VISTA, CTLA4, and PDL1 using immunohistochemistry (IHC)on 135 Formalin-Fixed Paraffin-Embedded (FFPE)tissue samples of High-grade serous carcinoma (HGSOC). VISTA, CTLA4, PDL1, PD1, CD8, CD4, and FOXP3 mRNA extracted from 429 patients with ovarian cancer in the Cancer Genome Atlas (TCGA) database was included as a validation cohort. Correlations between these checkpoints, tumor-infiltrating- lymphocytes (TILs), and survival were analyzed.Results and discussionCTLA4 was detectable in 87.3% of samples, VISTA in 64.7%, PD1 in 56.7%, and PDL1 in 48.1%. PDL1 was the only tested protein associated with an advanced stage (p=0.05). VISTA was associated with PDL1, PD1, and CTLA4 expressions (p=0.005, p=0.001, p=0.008, respectively), consistent with mRNA level analysis from the TCGA database. Univariate analyses showed only VISTA expression (p=0.04) correlated with overall survival (OS). Multivariate analyses showed that VISTA expression (p=0.01) and the coexpression of VISTA+/CTLA4+/PD1+ (p=0.05) were associated with better OS independently of the clinicopathological features. Kaplan-Meier analysis showed that the coexpression of the VISTA+/CTLA4+/PDL1+ and VISTA+/CTLA4+/PD1+ checkpoints on tumor cells (TCs)were associated with OS (p=0.02 and p
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- 2024
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28. Immunosignatures associated with TP53 status and co-mutations classify prognostically head and neck cancer patients
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Andrea Sacconi, Paola Muti, Claudio Pulito, Giulia Urbani, Matteo Allegretti, Raul Pellini, Nikolay Mehterov, Uri Ben-David, Sabrina Strano, Paolo Bossi, and Giovanni Blandino
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HNSCC ,Immunotherapy ,Immune checkpoint inhibitor ,p53 ,PDL1 ,c-MYC ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Immune checkpoint inhibitors (ICIs) are a therapeutic strategy for various cancers although only a subset of patients respond to the therapy. Identifying patients more prone to respond to ICIs may increase the therapeutic benefit and allow studying new approaches for resistant patients. Methods We analyzed the TCGA cohort of HNSCC patients in relation to their activation of 26 immune gene expression signatures, as well as their cell type composition, in order to define signaling pathways associated with resistance to ICIs. Results were validated on two cohorts of 102 HNSCC patients and 139 HNSCC patients under treatment with PD-L1 inhibitors, respectively, and a cohort of 108 HNSCC HPV negative patients and by in vitro experiments in HNSCC cell lines. Results We observed a significant association between the gene set and TP53 gene status and OS and PFS of HNSCC patients. Surprisingly, the presence of a TP53 mutation together with another co-driver mutation was associated with significantly higher levels of the immune gene expression, in comparison to tumors in which the TP53 gene was mutated alone. In addition, the higher level of TP53 mutated-dependent MYC signature was associated with lower levels of the immune gene expression signature. In vitro and three different patient cohorts validation analyses corroborated these findings. Conclusions Immune gene signature sets associated with TP53 status and co-mutations classify with more accuracy HNSCC patients. These biomarkers may be easily implemented in clinical setting.
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- 2023
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29. Advances in Immunotherapy for Hepatocellular Carcinoma (HCC)
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Fuat Bicer, Catrina Kure, Anil A. Ozluk, Bassel F. El-Rayes, and Mehmet Akce
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HCC ,immunotherapy ,PD1 ,PDL1 ,TIGIT ,LAG3 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related deaths in the world. More than half of patients with HCC present with advanced stage, and highly active systemic therapies are crucial for improving outcomes. Immune checkpoint inhibitor (ICI)-based therapies have emerged as novel therapy options for advanced HCC. Only one third of patients achieve an objective response with ICI-based therapies due to primary resistance or acquired resistance. The liver tumor microenvironment is naturally immunosuppressive, and specific mutations in cell signaling pathways allow the tumor to evade the immune response. Next, gene sequencing of the tumor tissue or circulating tumor DNA may delineate resistance mechanisms to ICI-based therapy and provide a rationale for novel combination therapies. In this review, we discuss the results of key clinical trials that have led to approval of ICI-based therapy options in advanced HCC and summarize the ongoing clinical trials. We review resistance mechanisms to ICIs and discuss how immunotherapies may be optimized based on the emerging research of tumor biomarkers and genomic alterations.
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- 2023
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30. Cancer-associated fibroblasts-derived CXCL12 enhances immune escape of bladder cancer through inhibiting P62-mediated autophagic degradation of PDL1
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Zhao Zhang, Yongbo Yu, Zhilei Zhang, Dan Li, Zhijuan Liang, Liping Wang, Yuanbin Chen, Ye Liang, and Haitao Niu
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Cancer-associated fibroblast ,CXCL12 ,PDL1 ,Autophagy ,P62 ,Immune escape ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Cancer-associated fibroblasts (CAFs), the predominant stromal cell of tumor microenvironment (TME), play an important role in tumor progression and immunoregulation by remodeling extracellular matrix (ECM) and secreting cytokines. However, little is known about the details of the underlying mechanism in bladder cancer. Methods Bioinformatics analysis was performed to analyze the prognostic value of CAFs and CXCL12 using GEO, TCGA and SRA databases. The effects of CXCL12 on bladder cancer progression were investigated through in vitro and in vivo assays. The biological mechanism of the effect of CXCL12 on PDL1 were investigated using western blotting, immunoprecipitation, RT-PCR, immunofluorescence, mass spectrometry, protein stability, and flow cytometry. Results The results demonstrated that CAFs-derived CXCL12 promoted cancer cell migration and invasion and upregulated PDL1. Mechanistically, upon binding to its specific receptor, CXCL12 activated the downstream JAK2/STAT3 pathway and rapidly up-regulated the expression of deubiquitinase CYLD. CYLD deubiquitinated P62 causing P62 accumulation, which in turn inhibited the autophagic degradation of PDL1. In vivo experiments demonstrated that blocking CXCL12 inhibited tumor growth, reduced tumor PDL1 expression and increased immune cell infiltration. Conclusions This study revealed a novel mechanism for the role of CXCL12 in P62-mediated PDL1 autophagic regulation. Combined application of CXCL12 receptor blocker and PD1/PDL1 blocker can more effectively inhibit PDL1 expression and enhance antitumor immune response. Targeting CAFs-derived CXCL12 may provide an effective strategy for immunotherapy in bladder cancer.
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- 2023
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31. PLP2 Could Be a Prognostic Biomarker and Potential Treatment Target in Glioblastoma Multiforme
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Qiao H and Li H
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immune infiltrates ,pdl1 ,programmed cell death-ligand 1 ,glioma ,molecular docking ,bioinformatics ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Hao Qiao, Huanting Li The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People’s Republic of ChinaCorrespondence: Huanting Li, Tel +86-17685811392, Email lihuanting2022@163.comObjective: This study aimed to discern the association between PLP2 expression, its biological significance, and the extent of immune infiltration in human GBM.Methods: Utilizing the GEPIA2 and TCGA databases, we contrasted the expression levels of PLP2 in GBM against normal tissue. We utilized GEPIA2 and LinkedOmics for survival analysis, recognized genes co-expressed with PLP2 via cBioPortal and GEPIA2, and implemented GO and KEGG analyses. The STRING database facilitated the construction of protein-protein interaction networks. We evaluated the relationship of PLP2 with tumor immune infiltrates using ssGSEA and the TIMER 2.0 database. An IHC assay assessed PLP2 and PDL-1 expression in GBM tissue, and the Drugbank database aided in identifying potential PLP2-targeting compounds. Molecular docking was accomplished using Autodock Vina 1.2.2.Results: PLP2 expression was markedly higher in GBM tissues in comparison to normal tissues. High PLP2 expression correlated with a decrease in overall survival across two databases. Functional analyses highlighted a focus of PLP2 functions within leukocyte. Discrepancies in PLP2 expression were evident in immune infiltration, impacting CD4+ T cells, neutrophils, myeloid dendritic cells, and macrophages. There was a concomitant increase in PLP2 and PD-L1 expression in GBM tissues, revealing a link between the two. Molecular docking with ethosuximide and praziquantel yielded scores of − 7.441 and − 4.295 kcal/mol, correspondingly.Conclusion: PLP2’s upregulation in GBM may adversely influence the lifespan of GBM patients. The involvement of PLP2 in pathways linked to leukocyte function is suggested. The positive correlation between PLP2 and PD-L1 could provide insights into PLP2’s role in glioma modulation. Our research hints at PLP2’s potential as a therapeutic target for GBM, with ethosuximide and praziquantel emerging as potential treatment candidates, especially emphasizing the potential of these compounds in GBM treatment targeting PLP2.Plain Language Summary: Glioblastoma is the most prevalent and aggressive malignant glioma. PLP2, a protein found to be upregulated in several cancers and neurological diseases, has drawn attention for its potential role in glioblastoma treatment. With advances in immunotherapy and improved understanding of tumor-immune system interactions, PD-1/PD-L1 inhibitors are gaining increasing interest for treating glioblastomas.In glioblastoma patients, overexpression of PLP2 may worsen overall survival rates. PLP2 is believed to be involved in key pathways related to leukocyte, and a connection was found between PLP2 and PD-L1, suggesting that PLP2 might influence glioblastomas through this interaction. The potential use of PD-1/PD-L1 inhibitors in treating glioblastomas has emerged as a result of these findings.Moreover, the study highlights the potential of drugs such as ethosuximide and praziquantel to target PLP2 in glioblastoma therapy. This research emphasizes the promising role of PLP2 as a therapeutic target for glioblastoma, where praziquantel and ethosuximide could be employed. Overall, the study presents a new therapeutic target for glioblastoma and demonstrates the potential of PD-1/PD-L1 inhibitors, praziquantel, and ethosuximide in this treatment approach.Keywords: immune infiltrates, PDL1, programmed cell death-ligand 1, glioma, molecular docking, bioinformatics
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- 2023
32. Immunosignatures associated with TP53 status and co-mutations classify prognostically head and neck cancer patients.
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Sacconi, Andrea, Muti, Paola, Pulito, Claudio, Urbani, Giulia, Allegretti, Matteo, Pellini, Raul, Mehterov, Nikolay, Ben-David, Uri, Strano, Sabrina, Bossi, Paolo, and Blandino, Giovanni
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HEAD & neck cancer , *PROGRAMMED cell death 1 receptors , *CANCER patients , *IMMUNE checkpoint inhibitors , *GENE expression - Abstract
Background: Immune checkpoint inhibitors (ICIs) are a therapeutic strategy for various cancers although only a subset of patients respond to the therapy. Identifying patients more prone to respond to ICIs may increase the therapeutic benefit and allow studying new approaches for resistant patients. Methods: We analyzed the TCGA cohort of HNSCC patients in relation to their activation of 26 immune gene expression signatures, as well as their cell type composition, in order to define signaling pathways associated with resistance to ICIs. Results were validated on two cohorts of 102 HNSCC patients and 139 HNSCC patients under treatment with PD-L1 inhibitors, respectively, and a cohort of 108 HNSCC HPV negative patients and by in vitro experiments in HNSCC cell lines. Results: We observed a significant association between the gene set and TP53 gene status and OS and PFS of HNSCC patients. Surprisingly, the presence of a TP53 mutation together with another co-driver mutation was associated with significantly higher levels of the immune gene expression, in comparison to tumors in which the TP53 gene was mutated alone. In addition, the higher level of TP53 mutated-dependent MYC signature was associated with lower levels of the immune gene expression signature. In vitro and three different patient cohorts validation analyses corroborated these findings. Conclusions: Immune gene signature sets associated with TP53 status and co-mutations classify with more accuracy HNSCC patients. These biomarkers may be easily implemented in clinical setting. [ABSTRACT FROM AUTHOR]
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- 2023
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33. Cancer-associated fibroblasts-derived CXCL12 enhances immune escape of bladder cancer through inhibiting P62-mediated autophagic degradation of PDL1.
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Zhang, Zhao, Yu, Yongbo, Zhang, Zhilei, Li, Dan, Liang, Zhijuan, Wang, Liping, Chen, Yuanbin, Liang, Ye, and Niu, Haitao
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STROMAL cell-derived factor 1 , *BLADDER cancer , *CANCER cell migration , *JAK-STAT pathway , *PROTEIN stability , *POTASSIUM antagonists - Abstract
Background: Cancer-associated fibroblasts (CAFs), the predominant stromal cell of tumor microenvironment (TME), play an important role in tumor progression and immunoregulation by remodeling extracellular matrix (ECM) and secreting cytokines. However, little is known about the details of the underlying mechanism in bladder cancer. Methods: Bioinformatics analysis was performed to analyze the prognostic value of CAFs and CXCL12 using GEO, TCGA and SRA databases. The effects of CXCL12 on bladder cancer progression were investigated through in vitro and in vivo assays. The biological mechanism of the effect of CXCL12 on PDL1 were investigated using western blotting, immunoprecipitation, RT-PCR, immunofluorescence, mass spectrometry, protein stability, and flow cytometry. Results: The results demonstrated that CAFs-derived CXCL12 promoted cancer cell migration and invasion and upregulated PDL1. Mechanistically, upon binding to its specific receptor, CXCL12 activated the downstream JAK2/STAT3 pathway and rapidly up-regulated the expression of deubiquitinase CYLD. CYLD deubiquitinated P62 causing P62 accumulation, which in turn inhibited the autophagic degradation of PDL1. In vivo experiments demonstrated that blocking CXCL12 inhibited tumor growth, reduced tumor PDL1 expression and increased immune cell infiltration. Conclusions: This study revealed a novel mechanism for the role of CXCL12 in P62-mediated PDL1 autophagic regulation. Combined application of CXCL12 receptor blocker and PD1/PDL1 blocker can more effectively inhibit PDL1 expression and enhance antitumor immune response. Targeting CAFs-derived CXCL12 may provide an effective strategy for immunotherapy in bladder cancer. [ABSTRACT FROM AUTHOR]
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- 2023
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34. Significance of NotchScore and JAG1 in predicting prognosis and immune response of low-grade glioma.
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Bo Shi, Fei Ge, Liangliang Cai, Yi Yang, Xiaohui Guo, Rui Wu, Zhehao Fan, Binjie Cao, Ning Wang, Yue Si, Xinyue Lin, Weibing Dong, and Haibo Sun
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NOTCH signaling pathway ,GENE expression profiling ,IMMUNE response ,GLIOMAS ,NOTCH genes - Abstract
Introduction: Low-grade glioma (LGG) is a prevalent malignant tumor in the intracranial region. Despite the advancements in treatment methods for this malignancy over the past decade, significant challenges still persist in the form of drug resistance and tumor recurrence. The Notch signaling pathway plays essential roles in many physiological processes as well as in cancer development. However, the significance of the pathway and family genes in LGG are poorly understood. Methods: We conducted gene expression profiling analysis using the TCGA dataset to investigate the gene set associated with the Notch signaling pathway. we have proposed a metric called "NotchScore" that quantifies the strength of the Notch signaling pathway and enables us to assess its significance in predicting prognosis and immune response in LGG. We downregulated JAG1 in low-grade gliomas to assess its influence on the proliferation and migration of these tumors. Ultimately, we determined the impact of the transcription factor VDR on the transcription of PDL1 through chip-seq data analysis. Results: Our findings indicate that tumors with a higher NotchScore, exhibit poorer prognosis, potentially due to their ability to evade the anti-tumor effects of immune cells by expressing immune checkpoints. Among the genes involved in the Notch signaling pathway, JAG1 has emerged as the most representative in terms of capturing the characteristics of both NotchScore and Notch pathways. The experimental results demonstrate that silencing JAG1 yielded a significant decrease in tumor cell proliferation in LGG cell lines. Our study revealed mechanisms by which tumors evade the immune system through the modulation of PDL1 transcription levels via the PI3K-Akt signaling pathway. Additionally, JAG1 potentially influences PDL1 in LGG by regulating the PI3KAkt signaling pathway and the expression of the transcription factor VDR. Discussion: These findings contribute to our understanding of immune evasion by tumors in LGG. The insights gained from this research may have implications for the development of therapeutic interventions for LGG. [ABSTRACT FROM AUTHOR]
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- 2023
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35. Long Non-Coding RNA LOC339059 Attenuates IL-6/STAT3-Signaling-Mediated PDL1 Expression and Macrophage M2 Polarization by Interacting with c-Myc in Gastric Cancer.
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Han, Haibo, Ding, Guangyu, Wang, Shanshan, Meng, Junling, Lv, Yunwei, Yang, Wei, Zhang, Hong, Wen, Xianzi, and Zhao, Wei
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RNA metabolism , *STOMACH tumors , *INTERLEUKINS , *STAT proteins , *FLOW cytometry , *SEQUENCE analysis , *MACROPHAGES , *CELL physiology , *CELLULAR signal transduction , *GENE expression profiling , *RESEARCH funding , *TUMOR suppressor genes , *TUMOR markers , *POLYMERASE chain reaction - Abstract
Simple Summary: In this study, we analyzed the role of LOC339059 in PDL1 expression and M2 polarization, which is mediated via the inhibition of IL-6/STAT3 signaling through interaction with c-Myc. Based on a retrospective cohort study, LOC339059 expression was determined to be down-regulated in primary gastric cancer tissues compared with adjacent tissues, and its low expression predicts a poor survival time after surgery. Furthermore, its level of expression was found to be correlated with the expression of some immune response genes. Functionally, LOC339059 acts as a tumor suppressor that can suppress malignant cell phenotypes, cell PDL1 expression, and macrophage M2 polarization. Mechanically, nucleus-localized LOC339059 interacts with c-Myc, competitively inhibiting the latter's ability to promote IL-6 transcription, thereby reducing IL-6/STAT3-mediated PDL1 expression and M2 polarization. Our results establish c-Myc as a pivotal factor at the crossroads of the LOC339059-mediated IL-6/STAT3-dependent regulation of the immune response. Background: Long non-coding RNA (lncRNA) was identified as a novel diagnostic biomarker in gastric cancer (GC). However, the functions of lncRNAs in immuno-microenvironments have not been comprehensively explored. In this study, we explored a critical lncRNA, LOC339059, that can predict the clinical prognosis in GC related to the modulation of PD-L1 and determined its influence upon macrophage polarization via the IL-6/STAT3 pathway. Methods: To date, accumulating evidence has demonstrated that the dysregulation of LOC339059 plays an important role in the pathological processes of GC. It acts as a tumor suppressor, regulating GC cell proliferation, migration, invasion, tumorigenesis, and metastasis. A flow cytometry assay showed that the loss of LOC339059 enhanced PDL1 expression and M2 macrophage polarization. RNA sequencing, RNA pull-down, RNA immunoprecipitation, Chip-PCR, and a luciferase reporter assay revealed the pivotal role of signaling alternation between LOC339059 and c-Myc. Results: A lower level of LOC339059 RNA was found in primary GC tissues compared to adjacent tissues, and such a lower level is associated with a poorer survival period (2.5 years) after surgery in patient cohorts. Moreover, we determined important immunological molecular biomarkers. We found that LOC339059 expression was correlated with PD-L1, CTLA4, CD206, and CD204, but not with TIM3, FOXP3, CD3, C33, CD64, or CD80, in a total of 146 GC RNA samples. The gain of LOC339059 in SGC7901 and AGS inhibited biological characteristics of malignancy, such as proliferation, migration, invasion, tumorigenesis, and metastasis. Furthermore, our data gathered following the co-culture of THP-1 and U937 with genomic GC cells indicate that LOC339059 led to a reduction in the macrophage cell ratio, in terms of CD68+/CD206+, to 1/6, whereas the selective knockdown of LOC339059 promoted the abovementioned malignant cell phenotypes, suggesting that it has a tumor-suppressing role in GC. RNA-Seq analyses showed that the gain of LOC339059 repressed the expression of the interleukin family, especially IL-6/STAT3 signaling. The rescue of IL-6 in LOC339059-overexpressing cells reverted the inhibitory effects of the gain of LOC339059 on malignant cell phenotypes. Our experiments verified that the interaction between LOC339059 and c-Myc resulted in less c-Myc binding to the IL-6 promoter, leading to the inactivation of IL-6 transcription. Conclusions: Our results establish that LOC339059 acts as a tumor suppressor in GC by competitively inhibiting c-Myc, resulting in diminished IL-6/STAT3-signaling-mediated PDL1 expression and macrophage M2 polarization. [ABSTRACT FROM AUTHOR]
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- 2023
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36. Advances in Immunotherapy for Hepatocellular Carcinoma (HCC).
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Bicer, Fuat, Kure, Catrina, Ozluk, Anil A., El-Rayes, Bassel F., and Akce, Mehmet
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HEPATOCELLULAR carcinoma , *CIRCULATING tumor DNA , *IMMUNE checkpoint inhibitors , *TUMOR markers , *IMMUNOTHERAPY - Abstract
Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related deaths in the world. More than half of patients with HCC present with advanced stage, and highly active systemic therapies are crucial for improving outcomes. Immune checkpoint inhibitor (ICI)-based therapies have emerged as novel therapy options for advanced HCC. Only one third of patients achieve an objective response with ICI-based therapies due to primary resistance or acquired resistance. The liver tumor microenvironment is naturally immunosuppressive, and specific mutations in cell signaling pathways allow the tumor to evade the immune response. Next, gene sequencing of the tumor tissue or circulating tumor DNA may delineate resistance mechanisms to ICI-based therapy and provide a rationale for novel combination therapies. In this review, we discuss the results of key clinical trials that have led to approval of ICI-based therapy options in advanced HCC and summarize the ongoing clinical trials. We review resistance mechanisms to ICIs and discuss how immunotherapies may be optimized based on the emerging research of tumor biomarkers and genomic alterations. [ABSTRACT FROM AUTHOR]
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- 2023
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37. Safety and efficacy of immune checkpoint blockade in patients with advanced nonsmall cell lung cancer and brain metastasis.
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Tsakonas, Georgios, Ekman, Simon, Koulouris, Andreas, Adderley, Helen, Ackermann, Christoph Jakob, and Califano, Raffaele
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NON-small-cell lung carcinoma ,BRAIN metastasis ,IMMUNE checkpoint proteins ,IMMUNE checkpoint inhibitors ,BRAIN cancer ,IPILIMUMAB - Abstract
The presence of brain metastases (BM) is a negative prognostic factor for patients with advanced nonsmall cell lung cancer (NSCLC). Their incidence seems to be higher in patients with oncogene‐driven tumours, especially those with EGFR‐mutated or ALK‐rearranged tumours. Although targeted treatments demonstrate significant efficacy regarding BM, they only apply to a minority of NSCLC patients. On the other hand, systemic therapies for nononcogenic‐driven NSCLC with BM have shown limited clinical benefit. In recent years, immunotherapy alone or combined with chemotherapy has been adopted as a new standard of care in first‐line therapy. This approach seems to be beneficial to patients with BM in terms of efficacy and toxicity. Combined immune checkpoint inhibition as well as the combination of immunotherapy and radiation therapy show promising results with significant, but overall acceptable toxicity. A pragmatic approach of allowing enrolment of patients with untreated or symptomatic BM in randomised trials evaluating immune checkpoint inhibitors strategies, possibly coupled with central nervous system‐related endpoints may be needed to generate data to refine treatment for this patient population. [ABSTRACT FROM AUTHOR]
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- 2023
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38. Expression patterns and clinical implications of PDL1 and DLL3 biomarkers in small cell lung cancer retrospectively studied: Insights for therapeutic strategies and survival prediction
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Kalliopi Domvri, Alexey V. Yaremenko, Apostolos Apostolopoulos, Savvas Petanidis, Sofia Karachrysafi, Nikoleta Pastelli, Theodora Papamitsou, Styliani Papaemmanouil, Sofia Lampaki, and Konstantinos Porpodis
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SCLC ,Biomarkers ,PDL1 ,DLL3 ,Histopathology ,Biopsy ,Science (General) ,Q1-390 ,Social sciences (General) ,H1-99 - Abstract
Lung cancer is a leading cause of cancer-related deaths globally, includes small cell lung cancer (SCLC), characterized by its aggressive nature and advanced disease at diagnosis. However, the identification of reliable biomarkers for SCLC has proven challenging, as no consistent predictive biomarker has been established. Nonetheless, certain tumor-associated antigens, including programmed death-ligand 1 (PDL1) and Delta-Like Ligand 3 (DLL3), show promise for targeted antibody-based immunotherapy. To ensure optimal patient selection, it remains crucial to comprehend the relationship between PDL1 and DLL3 expression and clinicopathological characteristics in SCLC. In this study, we investigated the expression patterns of PDL1 and DLL3 biomarkers in endobronchial samples from 44 SCLC patients, examining their association with clinical characteristics and survival. High PDL1 expression (>1%) was observed in 14% of patients, while the majority the SCLC patients (73%) exhibited high DLL3 expression (>75%). Notably, we found a positive correlation between high PDL1 expression (>1%) and overall survival. However, we did not observe any significant differences in the biomarkers expression concerning age, sex, disease status, smoking status, or distant metastases. Further subgroup analysis revealed that a high co-expression of both PDL1 (>1%) and DLL3 (100%) antigens was associated with improved overall survival. This suggests that SCLC expressing PDL1 and DLL3 antigens may exhibit increased sensitivity to therapy, indicating their potential as therapeutic targets. Thus, our findings provide novel insights into the simultaneous evaluation of PDL1 and DLL3 biomarkers in SCLC patients. These insights have significant clinical implications for therapeutic strategies, survival prediction, and development of combination immunotherapies.
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- 2024
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39. Immune infiltration, aggressive pathology, and poor survival outcomes in RECQL helicase deficient breast cancers
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Ayat Lashen, Abdulbaqi Al-Kawaz, Jennie N Jeyapalan, Shatha Alqahtani, Ahmed Shoqafi, Mashael Algethami, Michael Toss, Andrew R Green, Nigel P Mongan, Sudha Sharma, Mohammad R Akbari, Emad A Rakha, and Srinivasan Madhusudan
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RECQL ,CD8 ,FOXP3 ,IL17 ,PDL1 ,PD1 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
RECQL is essential for genomic stability. Here, we evaluated RECQL in 449 pure ductal carcinomas in situ (DCIS), 152 DCIS components of mixed DCIS/invasive breast cancer (IBC) tumors, 157 IBC components of mixed DCIS/IBC and 50 normal epithelial terminal ductal lobular units (TDLUs). In 726 IBCs, CD8+, FOXP3+, IL17+, PDL1+, PD1+ T-cell infiltration (TILs) were investigated in RECQL deficient and proficient cancers. Tumor mutation burden (TMB) was evaluated in five RECQL germ-line mutation carriers with IBC by genome sequencing. Compared with normal epithelial cells, a striking reduction in nuclear RECQL in DCIS was evident with aggressive pathology and poor survival. In RECQL deficient IBCs, CD8+, FOXP3+, IL17+ or PDL1+ TILs were linked with aggressive pathology and shorter survival. In germline RECQL mutation carriers, increased TMB was observed in 4/5 tumors. We conclude that RECQL loss is an early event in breast cancer and promote immune cell infiltration.
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- 2024
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40. Immunotherapy of Biliary Tract Cancer
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Mertens, Joachim C., Fritsch, Ralph, Theobald, Matthias, Series Editor, Moehler, Markus, editor, and Foerster, Friedrich, editor
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- 2023
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41. Circ_0001946 Promotes the Development of Acute Myeloid Leukemia by Upregulating PDL1
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Guohui Li, Conghui Zhu, Dan Qiao, and Renan Chen
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circ_0001946 ,pdl1 ,acute myeloid leukemia ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Objective: Circ_0001946 has been identified as an oncogenic factor, and the aim of this study was to explore the detailed roles and putative targets of circ_0001946 in acute myeloid leukemia (AML). Materials and Methods: Levels of circ_0001946 were examined in AML tissues and cells. Furthermore, the regulatory functions of circ_0001946 in AML were explored. The expression of circ_0001946 was evaluated in AML samples and a matched para-carcinoma control, as well as in AML cell lines and a human bone marrow stromal cell line using reverse transcription-quantitative polymerase chain reaction. Cell proliferation was examined using a CCK-8 kit, and migration/ invasion was measured by transwell assay. Furthermore, interactions between associated molecules were assessed using RNA pulldown, and the mRNA stability of the relevant gene was examined by mRNA stability assay. Results: Our data indicated that circ_0001946 was upregulated in AML specimens/cells. Additionally, overexpression of circ_0001946 promoted the proliferation, migration, and invasion of AML cells and, vice versa, these biological processes were suppressed by knockdown of circ_0001946. Furthermore, PDL1 is a potential downstream molecule of circ_0001946 in AML and its stability was improved by circ_0001946. The expression of PDL1 was increased in AML specimens and positively correlated with circ_0001946 expression. Moreover, biological behavioral alterations in AML cells induced by oe-circ_0001946 were abrogated by sh-PDL1 and the effects of sh-circ_0001946 were enhanced by treatment with sh-PDL1. Conclusion: Taken together, these data suggest that levels of circ_0001946 are elevated in AML and that circ_0001946 could promote the growth of AML cells. Furthermore, PDL1 is a novel downstream molecule of circ_0001946 in AML. Circ_0001946/PDL1 signaling may play crucial roles in tumor progression in AML and could be a novel candidate for targeted treatments for AML patients.
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- 2023
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42. Spotlight on Cemiplimab-rwlc in the Treatment of Non-Small Cell Lung Cancer (NSCLC): Focus on Patient Selection and Considerations
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Ahn J and Nagasaka M
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immunotherapy ,monotherapy ,combination chemotherapy ,pdl1 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Jeffrey Ahn,1 Misako Nagasaka1,2 1Department of Medicine, University of California Irvine School of Medicine, Chao Family Comprehensive Cancer Center, Orange, CA, USA; 2St. Marianna University School of Medicine, Kawasaki, JapanCorrespondence: Misako Nagasaka, Department of Medicine, University of California Irvine School of Medicine, Chao Family Comprehensive Cancer Center, 101 The City Drive South, Orange, CA, 92868, USA, Email nagasakm@hs.uci.eduAbstract: In metastatic non-small cell lung cancer (NSCLC), tumors that do not harbor driver mutations in EGFR or gene fusions in ALK and ROS, PD-1 and PD-L1 inhibitors have become a cornerstone in first line treatment, either as monotherapy or in combination with chemotherapy. This paper reviews cemiplimab-rwlc, the third PD-1/L1 inhibitor to be approved in the setting for first line treatment in NSCLC, as monotherapy or in combination therapy with chemotherapy, to provide a perspective on the subtle differences in patient population for the cemiplimab studies and consideration of its primary and subgroup results in the context of first line therapies for NSCLC.Keywords: immunotherapy, monotherapy, combination chemotherapy, PD-L1
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- 2023
43. Prognostic Value of KRAS Mutations in Relation to PDL1 Expression and Immunotherapy Treatment in Adenocarcinoma and Squamous Cell Carcinoma Patients: A Greek Cohort Study
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Theodora Tsiouda, Kalliopi Domvri, Efimia Boutsikou, Vasileios Bikos, Krystallia Kyrka, Konstantina Papadaki, Persefoni Pezirkianidou, Konstantinos Porpodis, and Angeliki Cheva
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lung cancer ,KRAS ,PDL1 ,immunotherapy ,survival ,Medicine - Abstract
Background: Factors that could predict which patients will benefit from Immune Checkpoint Inhibitors (ICIs) are not fully understood. This study aimed to investigate the prognostic value of KRAS biomarker in patients with advanced non-small cell lung cancer (NSCLC) in relation to clinical characteristics, treatment response and PDL1 expression. Patients and methods: The study included 100 patients with NSCLC who received immunotherapy with or without chemotherapy as 1st line treatment. In biopsy samples, the PDL1 biomarker expression rate and somatic mutations of KRAS gene were determined. Results: The mean age of the patients was 67 ± 8 years. Patients were all male and 66% were found with adenocarcinoma whereas 34% with squamous cell carcinoma. The KRAS G12C mutation was found with the highest percentage (73%). In the Kaplan-Meier survival analysis, patients with PDL1 > 49% in combination with a negative KRAS result had a median overall survival of 40 months compared to patients with a positive KRAS result (9 months, p < 0.05). In addition, patients diagnosed with adenocarcinoma, PDL1 < 49% and negative KRAS result had a median overall survival of 39 months compared to patients with a positive result (28 months, p < 0.05). Conclusions: Our study suggests that the presence of KRAS mutations in advanced NSCLC patients has a poor prognostic value, regardless of their PDL1 expression values, after receiving immunotherapy as first-line treatment.
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- 2024
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44. IGH::CD274 (PD‐L1) rearrangement in diffuse large B cell lymphoma and its therapeutic implication
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Xuemei Wu, Si Chen, Ping Chen, Han Zhang, Liying Zhang, Panjun Wang, Bingzong Li, Rong Rong, Yiting Wang, Xingping Lang, Kai Wang, Xiaohui Zhang, and Sheng Xiao
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DLBCL ,IGH ,PDL1 ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Abstract Diffuse large B cell lymphoma (DLBCL) expresses abundant programmed death ligand 1 (PD‐L1), which shields tumor cells from immune attacks through the PD‐L1/PD‐1 signaling axis. The mechanism of PD‐L1 overexpression includes the deletion of the 3′end of PD‐L1, which increases its mRNA stability, and the gain or amplification of PD‐L1. Previous studies found two cases of DLBCL carrying an IGH::PD‐L1 by whole genome sequencing. We describe two more such cases by a targeted DNA next‐generation sequencing (NGS) capable of detecting IGH rearrangements, leading to PD‐L1 overexpression. DLBCL with PD‐L1 overexpression is often resistant to R‐CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine and prednisolone). Our patients responded to a combination of R‐CHOP and a PD‐1 inhibitor.
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- 2023
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45. Real-World Outcomes of Stage IV NSCLC with PD-L1 ≥ 50% Treated with First-Line Pembrolizumab: Uptake of Second-Line Systemic Therapy
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Rebekah Rittberg, Bonnie Leung, Aria Shokoohi, Alexandra Pender, Selina Wong, Zamzam Al-Hashami, Ying Wang, and Cheryl Ho
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real-world evidence ,PDL1 ,pembrolizumab ,NSCLC ,second line ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Introduction: Platinum-based chemotherapy was compared to single-agent pembrolizumab in advanced non-small cell lung cancer (NSCLC) with PDL1 > 50% in KEYNOTE-024. In this trial, it was found that patients who received single-agent pembrolizumab had improved progression-free survival in addition to overall survival (OS). Based on KEYNOTE-024, only 53% of patients treated originally with pembrolizumab received second-line anticancer systemic therapy with an OS of 26.3 months. Based on these results, the objective of this study was to characterize real-world NSCLC patients who received second-line therapy after single-agent pembrolizumab. Methods: This was a retrospective cohort study considering stage IV NSCLC patients diagnosed with BC Cancer between 2018 and 2021 with PD-L1 ≥ 50% who received first-line single agent pembrolizumab. Patient demographics, cancer history, treatment administered, and survival were collected retrospectively. Descriptive statistics were produced. OS was calculated using Kaplan–Meier curves and compared using the log rank test. A multivariate model evaluated characteristics associated with the receipt of second-line therapy. Results: A total of 718 patients were diagnosed with Stage IV NSCLC and received at least one cycle of pembrolizumab. The median duration of treatment was 4.4 months, and the follow-up duration was 16.0 months. There were 567 (79%) patients who had disease progression, of whom 21% received second-line systemic therapy. Within the subset of patients with disease progression, the median duration of treatment was 3.0 months. It would be found that patients who received second-line therapy had better baseline ECOG performance status, were younger at diagnosis, and had a longer duration of pembrolizumab. Within the full population, the OS from the treatment initiation date was 14.0 months. OS was 5.6 months in patients who did not receive additional therapy after progression and 22.2 months in patients who received subsequent therapy. Baseline ECOG performance status was associated with improved OS in multivariate analysis. Conclusion: Based on this real-world Canadian population, 21% of patients received second-line systemic therapy, despite second-line therapy being associated with prolonged survival. In this real-world population, we found that 60% fewer patients received second-line systemic therapy when compared to KEYNOTE-024. Although differences always exist when comparing a clinical and non-clinical trial population, our findings suggest undertreating stage IV NSCLC patients.
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- 2023
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46. The NF-ĸB p50 subunit generated by KPC1-mediated ubiquitination and limited proteasomal processing, suppresses tumor growth
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Yelena Kravtsova-Ivantsiv, Gilad Goldhirsh, Ciprian Tomuleasa, Eli Pikarsky, and Aaron Ciechanover
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NF-ĸB p50 ,Tumor-suppression ,PDL1 ,KPC1 ,PROTAC ,Chemokines ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Cytology ,QH573-671 - Abstract
Abstract Nuclear factor-ĸB (NF-ĸB) is an important transcriptional regulator of key cellular processes, including cell cycle, immune response, and malignant transformation. We found that the ubiquitin ligase Kip1 ubiquitination-promoting complex subunit 1 (KPC1; also known as Ring finger protein 123 – RNF123) stimulates ubiquitination and limited proteasomal processing of the p105 NF-ĸB precursor to generate p50, the active subunit of the heterodimeric transcription factor. KPC1 binds to the ankyrin repeats’ (AR) domain of NF-ĸB p105 via a short binding site of 7 amino acids—968-WILVRLW-974. Though mature NF-ĸB is overexpressed and constitutively active in different tumors, we found that overexpression of the p50 subunit, exerts a strong tumor suppressive effect. Furthermore, excess of KPC1 that stimulates generation of p50 from the p105 precursor, also results in a similar effect. Analysis of transcripts of glioblastoma and breast tumors revealed that excess of p50 stimulates expression of many NF-ĸB-regulated tumor suppressive genes. Using human xenograft tumor models in different immune compromised mice, we demonstrated that the immune system plays a significant role in the tumor suppressive activity of p50:p50 homodimer stimulating the expression of the pro-inflammatory cytokines CCL3, CCL4, and CCL5 in both cultured cells and in the xenografts. Expression of these cytokines leads to recruitment of macrophages and NK cells, which restrict tumor growth. Finally, p50 inhibits the expression of the programmed cell death-ligand 1 (PDL1), establishing an additional level of a strong tumor suppressive response mediated by the immune system.
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- 2023
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47. Design and selection of anti-PD-L1 single-domain antibody and tumor necrosis factor superfamily ligands for an optimal vectorization in an oncolytic virus
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Christelle Remy, Elodie Pintado, Marshall Dunlop, Shirley Schön, Patricia Kleinpeter, Homa Rozanes, Laetitia Fend, Renée Brandely, Michel Geist, Delphine Suhner, Eline Winter, Nathalie Silvestre, Claire Huguet, Peter Fitzgerald, Eric Quéméneur, and Jean-Baptiste Marchand
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oncolytic virotherapy ,vaccinia virus ,single-domain antibody ,surfactant protein D ,PDL1 ,TNFSF ,Biotechnology ,TP248.13-248.65 - Abstract
Arming oncolytic viruses with transgenes encoding immunomodulators improves their therapeutic efficacy by enhancing and/or sustaining the innate and adaptive anti-tumoral immune responses. We report here the isolation, selection, and vectorization of a blocking anti-human PDL1 single-domain antibody (sdAb) isolated from PDL1-immunized alpacas. Several formats of this sdAb were vectorized into the vaccinia virus (VV) and evaluated for their programmed cell death protein 1 (PD1)/PD1 ligand (PDL1) blocking activity in the culture medium of tumor cells infected in vitro. In those conditions, VV-encoded homodimeric sdAb generated superior PDL1 blocking activity compared to a benchmark virus encoding full-length avelumab. The sdAb was further used to design simple, secreted, and small tumor necrosis factor superfamily (TNFSF) fusions with the ability to engage their cognate receptors (TNFRSF) only in the presence of PDL1-positive cells. Finally, PDL1-independent alternatives of TNFRSF agonists were also constructed by fusing different variants of surfactant protein-D (SP-D) oligomerization domains with TNFSF ectodomains. An optimal SP-D–CD40L fusion with an SP-D collagen domain reduced by 80% was identified by screening with a transfection/infection method where poxvirus transfer plasmids and vaccinia virus were successively introduced into the same cell. However, once vectorized in VV, this construct had a much lower CD40 agonist activity compared to the SP-D–CD40L construct, which is completely devoid of the collagen domain that was finally selected. This latest result highlights the importance of working with recombinant viruses early in the payload selection process. Altogether, these results bring several complementary solutions to arm oncolytic vectors with powerful immunomodulators to improve their immune-based anti-tumoral activity.
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- 2023
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48. Association between AHR Expression and Immune Dysregulation in Pancreatic Ductal Adenocarcinoma: Insights from Comprehensive Immune Profiling of Peripheral Blood Mononuclear Cells.
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Bartkeviciene, Arenida, Jasukaitiene, Aldona, Zievyte, Inga, Stukas, Darius, Ivanauskiene, Sandra, Urboniene, Daiva, Maimets, Toivo, Jaudzems, Kristaps, Vitkauskiene, Astra, Matthews, Jason, Dambrauskas, Zilvinas, and Gulbinas, Antanas
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PANCREATIC tumors , *ADENOCARCINOMA , *BIOMARKERS , *CYTOKINES , *MONONUCLEAR leukocytes , *PANCREATIC duct , *IMMUNE system , *GENE expression , *DUCTAL carcinoma , *GENE expression profiling , *RESEARCH funding , *DESCRIPTIVE statistics , *DATA analysis software , *T cells , *TRANSCRIPTION factors - Abstract
Simple Summary: This study investigated the role of aryl hydrocarbon receptor (AHR) expression in pancreatic ductal adenocarcinoma patients' peripheral blood immune cells. Peripheral blood mononuclear cells (PBMCs) were collected from 30 pancreatic ductal adenocarcinoma patients and 30 healthy controls. Patients were divided into Low and High/Medium AHR groups based on AHR gene expression in PBMCs. The Low AHR group exhibited distinct immune features, including increased free PD1 and PDL1 protein levels, lymphocyte/monocyte subtype alterations, decreased phagocytosis, increased nitric oxide production and expressed cytokine imbalances, particularly IL-4. These findings showed a potential link between the expression of AHRs and immune dysregulation in patients with pancreatic ductal adenocarcinoma. AHR may play a role in modulating the immune response against cancer. The insights gained from these investigations have the potential to pave the way for the development of innovative approaches for the treatment of pancreatic ductal adenocarcinoma. Pancreatic cancer, particularly pancreatic ductal adenocarcinoma (PDAC), has an immune suppressive environment that allows tumour cells to evade the immune system. The aryl-hydrocarbon receptor (AHR) is a transcription factor that can be activated by certain exo/endo ligands, including kynurenine (KYN) and other tryptophan metabolites. Once activated, AHR regulates the expression of various genes involved in immune responses and inflammation. Previous studies have shown that AHR activation in PDAC can have both pro-tumorigenic and anti-tumorigenic effects, depending on the context. It can promote tumour growth and immune evasion by suppressing anti-tumour immune responses or induce anti-tumour effects by enhancing immune cell function. In this study involving 30 PDAC patients and 30 healthy individuals, peripheral blood samples were analysed. PDAC patients were categorized into Low (12 patients) and High/Medium (18 patients) AHR groups based on gene expression in peripheral blood mononuclear cells (PBMCs). The Low AHR group showed distinct immune characteristics, including increased levels of immune-suppressive proteins such as PDL1, as well as alterations in lymphocyte and monocyte subtypes. Functional assays demonstrated changes in phagocytosis, nitric oxide production, and the expression of cytokines IL-1, IL-6, and IL-10. These findings indicate that AHR's expression level has a crucial role in immune dysregulation in PDAC and could be a potential target for early diagnostics and personalised therapeutics. [ABSTRACT FROM AUTHOR]
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- 2023
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49. Considerations for the clinical development of immunooncology agents in cancer.
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Pandiella, Atanasio, Calvo, Emiliano, Moreno, Victor, Amir, Eitan, Templeton, Arnoud, and Ocana, Alberto
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CLINICAL indications ,DRUG development ,CANCER cells ,IMMUNE system ,ANIMAL models in research - Abstract
Targeting of the immune system has shown to be a successful therapeutic approach in cancer, with the development of check point inhibitors (ICI) or T-cell engagers (TCE). As immuno-oncology agents modulate the immune system to attack cancer cells and do not act directly on oncogenic vulnerabilities, specific characteristics of these compounds should be taken in consideration during clinical development. In this review we will discuss relevant concepts including limitations of preclinical models, special pharmacologic boundaries, clinical development strategies such as the selection of clinical indication, line of treatment and backbone partner, as well as the endpoints and expected magnitude of benefit required at different stages of the drug development. In addition, future directions for early and late trial designs will be reviewed. Examples from approved drugs or those currently in clinical development will be discussed and options to overcome these limitations will be provided. [ABSTRACT FROM AUTHOR]
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- 2023
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50. A novel nomogram integrated with PDL1 and CEA to predict the prognosis of patients with gastric cancer.
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Di, Tian, Lai, Yue-rong, Luo, Qiu-yun, Chen, Zhi-gang, Du, Yong, Lin, Run-duan, Yang, Li-qiong, Zhang, Lin, and Sun, Jian
- Abstract
Introduction: This study aimed to develop a prognostic nomogram for patients with gastric cancer (GC) based on the levels of programmed death 1 ligand 1 (PDL1) and carcinoembryonic antigen (CEA). Methods: The nomogram was developed using data from a primary cohort of 247 patients who had been clinicopathologically diagnosed with GC, as well as a validation cohort of 63 patients. Furthermore, the nomogram divided the patients into three different risk groups for overall survival (OS)—the low-risk, middle-risk, and high-risk groups. Univariate and multivariate Cox hazard analyses were used to determine all of the factors included in the model. Decision curve analysis and receiver operating characteristic (ROC) curves were used to assess the accuracy of the nomogram. Results: The Kaplan–Meier survival analysis revealed that metastasis stage, clinical stage, and CEA and PDL1 levels were predictors for progress-free survival (PFS) and OS of patients with GC. Metastasis stage, clinical stage, and CEA and PDL1 levels were found to be independent risk factors for the PFS and OS of patients with GC in a multivariate analysis, and the nomogram was based on these factors. The concordance index of the nomogram was 0.763 [95% confidence interval (CI) 0.740–0.787]. The area under the concentration–time curve of the nomogram model was 0.81 (95% CI 0.780–0.900). According to the decision curve analysis and ROC curves, the nomogram model had a higher overall net efficiency in forecasting OS than clinical stage, CEA and PDL1 levels. Conclusion: In conclusion, we proposed a novel nomogram that integrated PDL1 and CEA, and the proposed nomogram provided more accurate and useful prognostic predictions for patients with GC. [ABSTRACT FROM AUTHOR]
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- 2023
- Full Text
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