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Chrysin is a natural flavonoid with anti-cancer effects. Despite its beneficial effects, little information is available regarding its immunogenic cell death (ICD) properties. In this work, we hypothesized that chrysin can potentiate radiotherapy(RT)-induced immunogenicity in melanoma cell line (B16-F10). We examined the effects of chrysin alone and in combination with radiation on ICD induction in B16-F10 cells. Cell viability was assessed using an MTT assay. Cell apoptosis and calreticulin (CRT) exposure were determined using flow cytometry. Western blotting and ELISA assay were employed to examine changes in protein expression. Combination therapy exhibited a synergistic effect, with an optimum combination index of 0.66. The synergistic anti-cancer effect correlated with increased cell apoptosis in cancer cells. Compared to the untreated control, chrysin alone and in combination with RT induced higher levels of DAMPs, such as CRT, HSP70, HMGB1, and ATP. The protein expression of p-STAT3/STAT3 and PD-L1 was reduced in B16-F10 cells exposed to chrysin alone and in combination with RT. Conditioned media from B16-F10 cells exposed to mono-and combination treatments elicited IL-12 secretion in dendritic cells (DCs), inducing a Th1 response. Our findings revealed that chrysin could induce ICD and intensify the RT-induced immunogenicity. [ABSTRACT FROM AUTHOR]

Case: Lynch syndrome (hereditary nonpolyposis colorectal cancer) is associated with extracolonic manifestations, but skeletal tumors are rare. Our patient, a 12-year-old boy with Lynch syndrome, developed osteosarcoma of the left femur. Treatment included cytotoxic chemotherapy, wide resection, and pembrolizumab. Two years later, he developed an aggressive lesion in the contralateral femur that was thought to be metastatic osteosarcoma but which histology revealed to be Langerhans cell histiocytosis. Conclusion: This case underscores the importance of advanced testing in patients with osteosarcoma and poor response to chemotherapy, and of tissue sampling when patients with a primary malignancy develop new bone lesions. Level of evidence: IV [ABSTRACT FROM AUTHOR]

Simple Summary: Lung cancer treatment options vary depending on the type and stage of the cancer. For non-small cell lung cancer (NSCLC), treatments may include surgery, chemotherapy, radiation therapy, targeted therapy, or a combination of these methods. Targeted therapies have demonstrated efficacy as adjuvant treatment in early-stage NSCLC when used alongside primary interventions such as surgery. In advanced stages of NSCLC, targeted therapies serve as a means of palliative care, enhancing quality of life and extending survival time. Our review article focuses on recent evidence of various treatment approaches and their impact on overall and progression-free survival in NSCLC patients, particularly targeting specific molecular and genetic alterations associated with NSCLC. Non-small cell lung cancer (NSCLC) presents a complex and diverse disease, exhibiting variations at individuals' cellular and histological levels. This complexity gives rise to different subtypes and genetic mutations, posing challenges for accurate diagnosis and effective treatment. Nevertheless, continuous progress in medical research and therapies is continually shaping the landscape of NSCLC diagnosis and management. The treatment of NSCLC has undergone significant advancements in recent years, especially with the emergence of targeted therapies that have shown remarkable efficacy in patients with actionable mutations. This has ushered in the era of personalized medicine in NSCLC treatment, with improvements in molecular and immunohistochemical techniques contributing to enhanced progression-free survival. This review focuses on the latest progress, challenges, and future directions in developing targeted therapies for NSCLC, including tyrosine kinase inhibitors (TKIs), DNA-damaging agents, immunotherapy regimens, natural drug therapy, and nanobodies. Furthermore, recent randomized studies have demonstrated enhanced overall survival in patients receiving different targeted and natural drug therapies. [ABSTRACT FROM AUTHOR]

Combining immune checkpoint inhibitors, specifically nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4), holds substantial promise in revolutionizing cancer treatment. This review explores the transformative impact of these combinations, emphasizing their potential for enhancing therapeutic outcomes across various cancers. Immune checkpoint proteins, such as PD1 and CTLA4, play a pivotal role in modulating immune responses. Blocking these checkpoints unleashes anticancer activity, and the synergy observed when combining multiple checkpoint inhibitors underscores their potential for enhanced efficacy. Nivolumab and ipilimumab harness the host's immune system to target cancer cells, presenting a powerful approach to prevent tumor development. Despite their efficacy, immune checkpoint inhibitors are accompanied by a distinct set of adverse effects, particularly immune-related adverse effects affecting various organs. Understanding these challenges is crucial for optimizing treatment strategies and ensuring patient well-being. Ongoing clinical trials are actively exploring the combination of checkpoint inhibitory therapies, aiming to decipher their synergistic effects and efficacy against diverse cancer types. This review discusses the mechanisms, adverse effects, and various clinical trials involving nivolumab and ipilimumab across different cancers, emphasizing their transformative impact on cancer treatment. [ABSTRACT FROM AUTHOR]

Owing to high global prevalence, incidence and associated mortality, cancer of head and neck particularly oral cancer remains a cardinal domain for research and trials. Immune-modulatory therapies that employ patients own immune system for therapeutic benefits in oral cancer seems promising. The aim of this review is to gauge the potential of immunotherapy as fourth domain of Oral cancer therapeutics. Articles were searched using suitable search terms in MEDLINE and Google Scholar database to include clinical trials, meta-analyses, and research in humans/animals/cell lines published in peer reviewed journals. A total of 97 articles were included in this review. Literature has several studies and trials where different types of immunotherapies has been attempted but it is crucial to identify precise biomarkers of genome based targeted agents and to find parameters to select patients who might benefit from immunotherapy. Also further research is required to estimate predictive value of tumor mutational burden and mutational signatures so as to aid in personalized prediction of oral cancer therapeutic response. [ABSTRACT FROM AUTHOR]

Simple Summary: This study focused on immune checkpoint inhibitor therapy effectiveness in patients with non-small cell lung cancer (NSCLC), particularly concerning programmed death ligand 1 (PD-L1) status and tumor mutational burden (TMB). The study utilized an Israeli multi-center registry spanning from January 2018 to December 2022, compiling detailed clinicopathological and molecular epidemiological data alongside treatment modalities. Clinical endpoints were assessed through Kaplan–Meier curves and Cox-regression models based on treatment assignment. While evidence on PD-L1 status and immune checkpoint inhibitors is established, data on TMB efficacy in both clinical trials and real-world settings are lacking. This study presents the largest academic real-world dataset on PD-L1 and TMB status in advanced NSCLC patients, suggesting comparable survival benefits despite limited direct comparisons. The efficacy of immune checkpoint inhibitor (ICI) therapy concerning programmed death ligand 1 (PD-L1) status is well established in patients diagnosed with non-small cell lung cancer (NSCLC). However, there remains a paucity of evidence regarding the efficacy concerning tumor mutational burden (TMB) in both clinical trials and real-world data (RWD). In the current article, clinicopathological and molecular epidemiological data were meticulously collected, and treatment modalities were meticulously recorded. The final analysis included a study population of 194 patients. Median age was 67 years (range 37–86), with the majority being male (71.13%), and 85.71% of patients were either current or former smokers at diagnosis. Adenocarcinoma accounted for most diagnoses (71.65%), followed by squamous cell carcinoma (24.23%). In terms of PD-L1 status, 42.78% had an expression level below 1%, 28.35% had an expression between 1–49%, and 28.87% had an expression above 50%. The TMB ranged from 0 to 75, with a median of 10.31 (range 0–75) for PD-L1 expression below 1%, with a median of 9.73 (range 0.95–39.63) for PD-L1 expression between 1–49%, and a median of 9.72 (range 0.95–48) for PD-L1 expression above 50%. Corresponding to patients with low PDL-1 less than 1% and low TMB (0–5), the median overall survival (mOS) was 16 (p = 0.18), and 15 months (p = 0.22), patients with medium PDL-1 (1–49%) and medium TMB (5–10), the mOS was 15 (p = 0.18) and 16 months (p = 0.22), patients with high PDL-1 (>50) and high TMB (>10), the mOS was 24 (p = 0.18) and 21 (p = 0.22) months. This study represents the largest academic RWD dataset concerning PD-L1 and TMB status in patients with locally advanced and metastatic NSCLC. [ABSTRACT FROM AUTHOR]

Introduction: Lung cancer is the most common type of cancer, causing worldwide mortality. Therefore, this study is necessary for continuing research into new effective and safe treatments. Recently, herbal medicines have been used for the treatment of various diseases such as cancer. This study aimed to investigate the potential anti-proliferative activity and investigate the mechanisms of hesperidin extract on the non-small lung cancer cells A549 and H460 vs. cisplatin via targeting the miR 34a/PD-L1/NF-κB signalling pathway. Material and methods: To determine the cytotoxic effects of the hesperidin extract on non-small lung cancer cells, sulphorhdamine B assay was performed. To show the inhibition of migration by hesperidin extract, wound healing assay was conducted. A quantitative polymerase chain reaction test was used to quantify the expressions of miR-34a, programmed cell death ligand-1 (PDL-1), epidermal growth factor receptor (EGFR), and P53 genes, which are involved in apoptosis pathway. Also, cell cycle assay was performed by using a flow cytometer. Results: The hesperidin extract could significantly inhibit proliferation of non-small lung cancer cells A549 and H460. Western blot assay demonstrated that hesperidin induced suppression of nuclear factor κB signalling pathway. The messenger RNA expression levels of MiR-34a and P53 were up-regulated significantly by hesperidin treatment, while the EGFR and P53 genes were down-regulated. The flow cytometer confirmed that cell cycle arrest occurred at the sub-G1 and G2 phases in A549 and H460, respectively. Conclusions: Our study demonstrated that hesperidin extract could significantly inhibit non-small lung cancer cell growth by induction of the apoptosis signalling pathway. Therefore, hesperidin might open novel strategies for effective and safe cancer treatment and reduce the adverse side effects of several chemotherapeutic treatments such as cisplatin. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a malignant disorder characterised by progressive immune dysregulation. The importance of programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) in MM has been documented in various populations, but studies have been limited to the Chinese cohort. In the present study, we examined the role of PD-1/PDL-1 in large cohorts of Chinese patients with MM and healthy controls to reveal a possible association with MM. Three hundred thirty-four MM patients and 202 healthy age-sex-matched subjects were enrolled in the present study. Serum levels of PD-1 and PD-L1 were quantified by ELISA. Percentages of T cells (CD4+ and CD8+ T cells) expressing PD-1 receptor were assessed by flow cytometry. Variants in PD-L1 (rs4143815) and PD-1 gene (rs2227981, rs2227982, rs7421861 and rs11568821) were genotyped by PCR-RFLP method. Patients with multiple myeloma had higher levels of PD-1 and PDL-1 than healthy controls, indicating an important role for programmed cell death protein-1 and its ligand in the pathogenesis of MM. T cells expressing PD-1 receptors were also significantly higher in MM patients than in controls. Mutants for PD-L1 (rs4143815) and PD-1 (rs2227982 and rs7421861) polymorphisms were significantly more common in MM than in HC. Interestingly, PD-L1 (rs4143815) and PD-1 (rs2227982 and rs7421861) variants were linked to higher sPD-L1 and sPD-1 levels, respectively. PD-1/PD-L1 levels are significantly higher in MM patients and could be a promising biomarker for the disease. Variants of PD-L1 and PD-1 are linked to serum-soluble proteins and are associated with the development of MM. [ABSTRACT FROM AUTHOR]

Background: Immune escape, a process by which tumor cells evade immune surveillance, remains a challenge for cancer therapy. Tumor cells produce extracellular vesicles (EVs) that participate in immune escape by transferring bioactive molecules between cells. EVs refer to heterogeneous vesicles that participate in intercellular communication. EVs from tumor cells usually carry tumor antigens and have been considered a source of tumor antigens to induce anti-tumor immunity. However, evidence also suggests that these EVs can accelerate immune escape by carrying heat shock proteins (HSPs), programmed death-ligand 1 (PD-L1), etc. to immune cells, suppressing function and exhausting the immune cells pool. EVs are progressively being evaluated for therapeutic implementation in cancer therapies. EVs-based immunotherapies involve inhibiting EVs generation, using natural EVs, and harnessing engineering EVs. All approaches are associated with advantages and disadvantages. The EVs heterogeneity and diverse physicochemical properties are the main challenges to their clinical applications. Short conclusion: Although EVs are criminal; they can be useful for overcoming immune escape. This review discusses the latest knowledge on EVs population and sheds light on the function of tumor-derived EVs in immune escape. It also describes EVs-based immunotherapies with a focus on engineered EVs, followed by challenges that hinder the clinical translation of EVs that are essential to be addressed in future investigations. 1vprELZ8YBVj6rfjBJ553Y Video Abstract [ABSTRACT FROM AUTHOR]

Background: Immunotherapy targeting the PD-1/PD-L1 pathway is a standard of care in a number of metastatic malignancies, but less than a fifth of patients are expected to respond to ICIs (Immune Checkpoint Inhibitors). In a clinical trial, combining the anti-TIGIT (T cell immunoreceptor with Ig and ITIM domains) Mab (monoclonal antibody) tiragolumab with atezolizumab improved outcomes in non-small cell lung cancer. In preclinical models, SBRT (Stereotactic Body Radiation Therapy) could increase expression levels of the inhibitory co-receptors TIGIT and PD-L1. We aim to assess the combination of tiragolumab with atezolizumab and SBRT in metastatic, previously treated by ICIs, non-small cell lung cancer, head and neck cancer, bladder cancer, and renal cell cancer. Methods: This phase I study (ClinicalTrials.gov NCT05259319) will assess the efficacy and safety of the combination of atezolizumab with tiragolumab and stereotactic body radiation therapy in patients with histologically proven metastatic non-small cell lung cancer, renal cell cancer, bladder cancer, and head and neck cancer previously treated. First part: 2 different schedules of SBRT in association with a fixed dose of atezolizumab and tiragolumab will be investigated only with metastatic non-small cell lung cancer patients (cohort 1). The expansion cohorts phase will be a multicentric, open-label study at the recommended scheme of administration and enroll additional patients with metastatic bladder cancer, renal cell cancer, and head and neck cancer (cohort 2, 3 and 4). Patients will be treated until disease progression, unacceptable toxicity, intercurrent conditions that preclude continuation of treatment, or patient refusal in the absence of progression or intolerance. The primary endpoint of the first phase is the safety of the combination in a sequential or concomitant scheme and to determine the expansion cohorts phase recommended scheme of administration. The primary endpoint of phase II is to evaluate the efficacy of tiragolumab + atezolizumab + SBRT in terms of 6-month PFS (Progression-Free Survival). Ancillary analyses will be performed with peripheral and intratumoral immune biomarker assessments. Trial registration: This study is registered on ClinicalTrials.gov: NCT05259319, since February 28th, 2022. [ABSTRACT FROM AUTHOR]

Background: IGF2BP3 expression is associated with poor prognosis in cancers of multiple tissue origins. However, the precise mechanism of its co-carcinogenic action in bladder cancer is unknown. Methods: We aimed to demonstrate the relationship between IGF2BP3 expression and pan-cancer using The Cancer Genome Atlas (TCGA) database. We next validated IGF2BP3 expression in the Gene Expression Omnibus (GEO) database (GSE3167). Receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic values of IGF2BP3. Cox and logistic regression were used to explore the factors affecting the prognosis. Protein–protein interactions (PPIs) network was constructed by STRING. Enrichment analyses were performed to infer involved pathways and functional categories of IGF2BP3 using the cluster Profiler package. We applied single-sample gene set enrichment analysis (ssGSEA) algorithm and TIMER database to evaluate the expression level of immune genes. Results: Pan-cancer analyses reveal that IGF2BP3 was higher in most cancer types, including bladder cancer, and the same results were found in GSE3167. The area under the ROC curve of IGF2BP3 was 0.736, which indicated that IGF2BP3 may be a potential diagnostic biomarker. High IGF2BP3 expression was associated with poorer overall survival (OS) (P = 0.015). For validation, we collected 95 bladder cancer samples and found that IGF2BP3 expression was higher in bladder cancer tissues than that in non-tumor bladder tissues by immunohistochemistry staining. We found a positive correlation between the expression level of IGF2BP3 and the clinical stage of bladder cancer. Immunocyte infiltration analysis showed that high IGF2BP3 expression was correlated with regulating the infiltration level of immune cell, including neutrophil cells and macrophages. IGF2BP3 promotes migration and invasion of bladder cancer cells, while IGF2BP3 inhibition had the opposite effects. Higher IGF2BP3 expression was closely associated with advanced TNM stage. Conclusion: IGF2BP3 overexpression was related to disease progression and poor prognosis, as well as infiltration of immune cells in bladder cancer. IGF2BP3 can be a promising independent prognostic biomarker and potential treatment target for bladder cancer. [ABSTRACT FROM AUTHOR]

Pazopanib, an inhibitor of the VEGF receptor tyrosine kinase, has demonstrated significant antitumor effects in lung cancer. However, its application as a standard treatment for this type of cancer is limited by its drug resistance and toxicity. Metformin has the potential to combat lung cancer by modifying the tumor's immune microenvironment. In this study, we investigated the potential antitumor effects and the associated underlying molecular mechanisms of the combination of pazopanib and metformin in lung cancer. In vitro studies were conducted using the A549 and H460 lung cancer cell lines, whereas urethane-induced lung cancer-bearing mice were used for in vivo assessments. The urethane-induced mice received oral administration of pazopanib (50 mg/kg) and/or metformin (250 mg/kg) for a duration of 21 days. The results indicated that the MTT assay demonstrated a combined cytotoxic effect of the pazopanib/metformin combination in H460 and A549 cells, as evidenced by CI and DRI analyses. The observed increase in annexin V levels and the corresponding increase in Caspase-3 activity strongly suggest that this combination induced apoptosis. Furthermore, the pazopanib/metformin combination significantly inhibited the p-Akt/NF-κB/IL-6/STAT3, HIF1α/VEGF, and TLR2/TGF-β/PD-L1 pathways while also increasing CD8 expression in vivo. Immunohistochemical analysis revealed that these antitumor mechanisms were manifested by the suppression of the proliferation marker Ki67. In conclusion, these findings revealed that metformin augments the antitumor efficacy of pazopanib in lung cancer by simultaneously targeting proliferative, angiogenic, and immunogenic signaling pathways, metformin enhances the antitumor effectiveness of pazopanib in lung cancer, making it a promising therapeutic option for lung cancer. [Display omitted] • The efficacy of pazopanib in lung cancer is limited due to drug toxicity. • Pazopanib and metformin combination displayed synergistic cytotoxic effects in lung cancer cells. • Combination therapy induced apoptosis and reduced proliferation in lung cancer models. • Pazopanib/metformin combination suppressed p-Akt/ NF-κB/ STAT3/ PD-L1signal pathway. • Pazopanib and metformin combination is a promising treatment option for lung cancer. [ABSTRACT FROM AUTHOR]

Breast cancer is the most frequent kind of invasive cancer in women. Biomarker monitoring and prognosis provide outstanding clinical information that may be employed to battle various cancers. This study aimed to examine a variety of biomarkers utilizing a multiplex bead array. BTLA, CD27, CD28, TIM-3, HVEM, CD40, LAG-3, TLR-2, PD-1, CD80, CD86, PDL-1, PDL-2, and ICOS are common biomarker checkpoint proteins found in a selective panel. This panel examined a research group of 59 patients with BC and 17 healthy people. The expression patterns of a handful of the fourteen biomarkers varied considerably between people with BC and healthy controls. With P-values of (p= 0.05), (p= 0.02), (p= 0.01), and (p= 0.02), general features of the two groups of malignant and non-malignant patients revealed significant correlations in parameters such as the age of first menstruation, pregnancy, menopausal status, and hormone replacement treatment. With P- values, there was a substantial rise in BTLA, HVEM, TLR-2, and PDL-1 serum levels, as well as a significant drop in CD86. Furthermore, these markers indicated a significant relationship with the clinic-pathological aspects of the patients. With a P-value of 0.0002, both BTLA and HVME showed a statistically significant connection with hormone receptor phenotypes. For ER status, BTLA, CD86, and PDL1 had equivalent significance values of (p= 0.0148), (p= 0.0166), and (p= 0.0001). BTLA was related to lymph node involvement (p=0.0397), whereas TLR2 was associated with HER2 status (p=0.0332). BTLA, HVEM, TLR-2 CD86, and PDL-1 may be valuable biomarkers for cancer monitoring and prognosis. [ABSTRACT FROM AUTHOR]

Programmed cell death protein‐1/programmed death‐ligand‐1 (PD‐1/PDL‐1) signalling pathway has gained attention in prostate cancer. The relationship between pSTAT‐1, pSTAT‐3 expressions and PTEN loss with PDL‐1 expression was assessed and the effects of the pathways on prostate cancer prognosis were evaluated. Patients who underwent radical prostatectomy between 2011 and 2017 were included in our study. Prostatectomy materials were evaluated using immunohistochemical staining of pSTAT‐1, pSTAT‐3, PTEN, and PDL‐1. The relationship between PDL‐1 and pSTAT‐1, pSTAT‐3 expressions and PTEN loss was evaluated. Additionally, factors affecting biochemical recurrence‐free survival and clinical progression‐free survival were analysed. Within100 patients, 9 of 11 patients with PDL‐1 expression also had intermediate‐high pSTAT‐1 staining intensity, and those with PDL‐1 expression had higher pSTAT‐1 staining intensity than those without (81.9% vs. 56.2%, p = 0.014). In univariate analysis, pSTAT‐1, pSTAT‐3 and PDL‐1 expressions had significant impact on biochemical recurrence‐free and clinical progression‐free survival. In multivariate analysis, pSTAT‐1 staining intensity with radical prostatectomy ISUP grade in terms of biochemical recurrence‐free survival and the pSTAT‐1 H‐score with radical prostatectomy ISUP grade in terms of clinical progression‐free survival were independent risk factors. Moderate‐high expression of pSTAT‐1 was closely associated with PDL‐1 expression, and pSTAT‐1 was also a predictor of biochemical recurrence and clinical progression. [ABSTRACT FROM AUTHOR]

The expression pattern of the markers p19, Ki-67, MSX1, MSX2, PDL1, pRB, and CYCLINA2 was quantitatively and semiquantitatively analyzed in histologic sections of the developing and postnatal human eye at week 8, in retinoblastoma, and in various uveal melanomas post hoc studies by double immunofluorescence. The p19 immunoreactivity characterized retinal and/or choroidal cells in healthy and tumor tissues: expression was lower in the postnatal retina than in the developing retina and retinoblastoma, whereas it was high in epithelioid melanomas. Ki67 expression was high in the developing eye, retinoblastoma, and choroidal melanomas. MSX1 and MSX2 expression was similar in the developing eye and retinoblastoma, whereas it was absent in the postnatal eye. Their different expression was evident between epithelioid and myxoid melanomas. Similarly, PDL1 was absent in epithelioid melanomas, whereas it was highly expressed in developing and tumor tissues. Expression of pRB and CYCA2 was characteristic of developing and tumorous eye samples but not of the healthy postnatal eye. The observed expression differences of the analyzed markers correlate with the origin and stage of cell differentiation of the tissue samples. The fine balance of expression could play a role in both human eye development and ocular tumorigenesis. Therefore, understanding their relationship and interplay could open new avenues for potential therapeutic interventions and a better understanding of the mechanisms underlying the developmental plasticity of the eye and the development of neoplasms. [ABSTRACT FROM AUTHOR]

Purpose: Immune checkpoint inhibitors (ICIs) have prolonged the survival of patients with various carcinomas, including non-small cell lung cancer (NSCLC), and have caused a paradigm shift in cancer treatment. Although programmed death-ligand 1 (PD-L1) expression in tumor cells is a predictive marker of therapeutic efficacy, additional predictive markers are required. This study aimed to explore the role of immunological and nutritional parameters in the prediction of treatment response. Methods: Patients diagnosed with NSCLC and treated with pembrolizumab were examined retrospectively. Body weight was measured 4–6 weeks before the start of the first treatment, immediately before treatment, and 4–6 weeks after the start of the first treatment. Progression-free survival (PFS) was defined as the time from the start of pembrolizumab treatment to the last follow-up date or until disease progression. Statistical analyses were performed to confirm the association between various factors and association between these factors and PFS. Results: Thirty-eight patients with advanced NSCLC were included. We observed a significant association of weight loss and PD-L1 expression with PFS in the multivariate analysis. A significant correlation was found between the advanced lung cancer inflammation index and neutrophil-to-lymphocyte ratio. A weight loss of > 5% after the start of treatment was significantly associated with worse PFS. Conclusions: Weight loss is an important negative prognostic factor in patients with NSCLC receiving immunotherapy. Weight maintenance may be important for good ICI treatment efficacy, and future interventions in cancer cachexia are expected to further enhance the treatment efficacy of ICIs. [ABSTRACT FROM AUTHOR]

Thymic Epithelial Tumors (TETs) represent a rare tumor family, originating from the epithelial component of the thymus gland. Clinicopathologically, they are segregated into six major subtypes, associated with distinct histological features and clinical outcomes. Their emergence and evolution are accompanied by the generation of a complex tumor microenvironment (TME), dominated by phenotypically and functionally divergent immune cellular subsets, in different maturation states and in analogies that vary significantly among different subtypes. These heterogenous leukocyte populations exert either immune-permissive and tumor-suppressive functions or vice versa, and the dynamic equilibrium established among them either dictates the tumor immune milieu towards an immune-tolerance state or enables the development of a productive spontaneous tumoricidal response. The immunologically "hot" microenvironment, defining a significant proportion of TETs, makes them a promising candidate for the implementation of immune checkpoint inhibitors (ICIs). A number of phase I and II clinical trials have already demonstrated significant, type-specific clinical efficacy of PD-L1 inhibitors, even though substantial limitations in their utilization derive from their immune-mediated adverse effects. Moreover, the completed clinical studies involved relatively restricted patient samples and an expansion in the enrolled cohorts is required, so that more trustworthy conclusions regarding the benefit from ICIs in TETs can be extracted. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a genetically heterogeneous clonal disease defined by the proliferation and accumulation of immature hematopoietic cells in the bone marrow and blood. This study aimed to evaluate the CD47 and CD274 (PD-L1) expression in Iraqi AML patients and its role in the disease and evasion of malignant cells from immune system. The study was conducted on 85 patients diagnosed with leukemia, 25 of them were excluded as they had taken chemotherapy for less than a week and because the proportion of tumor cells was less than 20%. Virtually, it was conducted on 60 patients with AML and 20 healthy individuals as a control group. The expression of CD47 and CD274 (PD-L1) was evaluated using flow cytometry in the peripheral blood of AML samples only. Also MMP-2 level in serum was evaluated via ELISA in both AML and control samples. The expression of CD47 and CD274 in AML patients was found to be high. Analysis of CD274 (PDL1) expression in blast populations showed a significant increase in the proportion of CD274 (PD-L1) positive blast cells in isolated peripheral blood samples (66.3050 ± 1.94522). Also, the CD47 expression on blast cells in AML was recorded as significantly high (64.9333±2.05873). For MMP-2 (ng/ml) level in serum, the mean level non-significantly increased in AML as compared to the control group (102.677±8.719; 92.191±5.161) respectively. [ABSTRACT FROM AUTHOR]

Introduction: Immune checkpoint inhibitor (ICI) therapy is an established treatment for advanced non‐small‐cell lung cancer (NSCLC) and programmed death ligand‐1 (PD‐L1) expression is a recognized biomarker to determine response to therapy. We retrospectively analyzed NSCLC patients in the Malaysia Lung Cancer Registry (MLCR) and report on the clinical characteristics associated with PD‐L1 expression and ICI use in Malaysia, a low‐ to middle‐income country. Methods: All 901 NSCLC patients in the MLCR who were diagnosed from January 1, 2017 to December 31, 2020 from 14 hospitals across the country were analyzed. Results: Out of 901 patients, 505 had PDL‐1 testing done with complete data available only in 489 patients. The most common histology was adenocarcinoma (84.7%) followed by squamous cell carcinoma (10.2%). The majority (95%) presented with stage 3 or 4. The number and percentage of patients with PDL‐1 tumor proportion scores of ≥50%, 1–49%, and <1% were 138 (28.2%), 158 (32.3%), and 193 (39.5%), respectively. In multivariate analysis, the presence of genomic mutation is the only independent characteristic associated with negative PD‐L1 expression (crude odds ratio 0.579, 95% confidence interval 0.399–0.840, p = 0.004). Of 292 patients eligible for ICI therapy, only 100 patients (34.2%) received ICIs. Seventy‐eight patients received ICI therapy as first‐line treatment, 15 patients as second‐line treatment, and 7 patients as third‐line treatment. Conclusions: This is the first analysis on PD‐L1 expression and ICI use in Malaysia. Despite the proven efficacy of ICI therapy, only 56% of our patients had PD‐L1 tests performed and only 34.2% of eligible patients received ICIs. [ABSTRACT FROM AUTHOR]

The characterization of the receptors negatively modulating lymphocyte function is rapidly advancing, driven by success in tumor immunotherapy. As a result, the number of immune checkpoint receptors characterized from a functional perspective and targeted by innovative drugs continues to expand. This review focuses on the less explored area of the signaling mechanisms of these receptors, of those expressed in T cells. Studies conducted mainly on PD-1, CTLA-4, and BTLA have evidenced that the extracellular parts of some of the receptors act as decoy receptors for activating ligands, but in all instances, the tyrosine phosphorylation of their cytoplasmatic tail drives a crucial inhibitory signal. This negative signal is mediated by a few key signal transducers, such as tyrosine phosphatase, inositol phosphatase, and diacylglycerol kinase, which allows them to counteract TCR-mediated activation. The characterization of these signaling pathways is of great interest in the development of therapies for counteracting tumor-infiltrating lymphocyte exhaustion/anergy independently from the receptors involved. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To show the effect of programmed cell death protein-1 ligand level survival times in patients with metastatic non-small cell lung cancer receiving chemotherapy, to determine the relationship between programmed cell death protein-1 ligand level, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio. MATERIAL AND METHODS: The data of 158 patients who received chemotherapy for metastatic non-small cell lung cancer were evaluated retrospectively. Clinical and demographic data, programmed cell death protein-1 ligand expression levels, and follow-up periods of the patients were recorded. The patients were divided into 2 groups according to programmed cell death protein-1 ligand levels. RESULTS: In all patients, progression-free survival was 5.6 months and overall survival was 18.8 months. Patients with low programmed cell death protein-1 ligand had a longer progression-free survival than patients with high programmed cell death protein-1 ligand (P = .038). In the gemcitabine and taxane groups, patients with low programmed cell death protein-1 ligand had a longer progression-free survival than patients with high programmed cell death protein-1 ligand (P = .047). There was a significant correlation between neutrophil-to-lymphocyte ratio and programmed cell death protein-1 ligand levels. In the groups with high programmed cell death protein-1 ligand, patients with low neutrophil-to-lymphocyte ratio levels had higher overall survival than patients with high neutrophil-to-lymphocyte ratio level (P = .043). Also, there was a significant difference between the overall survival patients with low and high platelet-to-lymphocyte ratio levels (P = .520). CONCLUSION: In patients with metastatic non-small cell lung cancer whose programmed cell death protein-1 ligand levels and neutrophil-to-lymphocyte ratio levels are low, immunogenic chemotherapies such as gemcitabine and taxane can be tried as an alternative treatment. [ABSTRACT FROM AUTHOR]

Lung cancers have high incidence and high mortality rates. The immune checkpoints as programmed death ligand 1 (PDL-1) can suppress the tumor immune reaction. So, their blocking seems to be a way to treat tumors. This study assesses PDL-1 immunohistochemical expression in lung cancer, and its correlation with prognosis. It included 62 specimens of lung cancer in Hospitals of Mansoura Faculty of Medicine, Egypt. Seventy-one percent of cases showed positive PDL-1 and about 59.1% of them showed high expression. PDL-1 expression in NSCLC was significantly higher than in SCLC (P = 0.019). There were no significant associations between PDL-1 expression and other clinicopathological parameters. A significant mild positive correlation between PDL-1 and EGFR marker was found (P= 0.006). The mean overall survival in cases with positive PDL-1 was lower than negative cases (P = 0.37). Also, progression-free survival was lower among PDL-1 positive cases compared to negative cases (P = 0.5). This study reports that immune checkpoint, PDL-1 is overexpressed in lung cancer especially NSCLC. It is correlated with EGFR overexpression. PDL-1 could have potential to be an effective immune target for lung cancer immunotherapy. But the presence of PD-L1-negative tumors highlights the importance of searching for alternative or combination treatment strategies. Abbreviations: AC: Adenocarcinoma; COPD: Chronic Obstructive Pulmonary Diseases; CTLA-4: Cytotoxic T-lymphocyte-associated protein 4; EGFR: Epidermal Growth Factor Receptor; IHC: Immunohistochemical; NSCLC: Non-Small Cell Lung Cancer; OS: Overall Survival; PD1: Programmed Death 1; PDL-1: Programmed Death ligand 1; PFS: Progression Free Survival; SCC: Squamous cell carcinoma; SCLC: Small Cell Lung Cancer; SD: Standard Deviation; TCR: T-cell receptor; TPS: Tumor Proportion Score. [ABSTRACT FROM AUTHOR]

Résumé: L'immunothérapie anticancéreuse est en plein essor grâce au développement des inhibiteurs du checkpoint immunitaire. Ces anticorps monoclonaux ciblant notamment le CTLA-4 et le PD-1 permettent de stimuler l'immunité antitumorale de l'hôte. Ils ont d'abord transformé le pronostic du mélanome métastatique et de certains cancers broncho-pulmonaires à petites cellules. Ces bénéfices s'étendent progressivement à de nombreux autres organes et notamment aux cancers du tractus gastro-intestinal. Bien que leur efficacité réside dans leur effet immunologique, la contribution du microbiote intestinal est désormais indéniable, jouant un rôle sur l'efficacité et la tolérance des inhibiteurs du checkpoint immunitaire. En effet, certains patients peuvent développer des effets indésirables immuno-médiés et notamment des entérocolites qui miment une maladie inflammatoire chronique de l'intestin. Cet article décrit plus particulièrement les liens entre microbiote intestinal et inhibiteurs du checkpoint immunitaire. Cancer immunotherapy use and more specifically checkpoint inhibitor is currently rising based on dramatic improvement of prognosis of many cancers such as metastatic melanoma and some subtypes of lung cancer. Checkpoint inhibitors are now implemented in many other cancers including those of the gastrointestinal tract. The contribution of intestinal microbiome has been suggested through many studies allowing some microbial fingerprints to predict efficacy and safety. Indeed, some patients may experience immune-related adverse events notably enterocolitis mimicking inflammatory bowel disease. This paper describes the specific contribution of intestinal microbiome to efficacy and safety of checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

PD-1/PDL-1 inhibitors and cardiotoxicity; molecular, etiological and management outlines. [Display omitted] The US Food and Drug Administration (FDA) has approved several immunotherapeutic drugs for cancer since 2010, and many more are still being evaluated in other clinical studies. These inhibitors significantly increase response rates and result in the treatment of patients with advanced cancer. However, cancer immunotherapy leads to essential cardiac toxicity properties that have become distinct from other cancer patients' care and are mostly related to their etiology. As potential implications, the occurrence of cardiovascular adverse events is particularly challenging and needs a comprehensive understanding of overall cancer-related etiology, clinical outcomes with different variable severity, and management. In terms of improving the overall survival of patients with cancer, clinicians should be careful in selecting either programmed cell death-1 (PD-1) or its programmed cell death ligand (PDL-1) inhibitors by evaluating their risk and clinical benefit for early intervention and decrease the level of morbidity and mortality of their patients. This review focuses on the effectiveness of PD-1/PL-1 antibodies and associated cardiotoxicity adverse events, including etiological mechanisms, diagnosis, and treatment. [ABSTRACT FROM AUTHOR]

Objective(s): Checkpoint blocking is considered a revolutionary method in cancer treatment. This method eliminates cancer cells by maintaining the sensitivity of immune cells. Today, cell therapy through checkpoint blocking is known as the most efficient method of cancer treatment. The programmed cell death protein-1(PD-1), as an immune check protein, has a vital role in weakening the immune responses by reducing the number of stimulated T cells. In normal situations, a decline in the immune responses can cause induced tolerance and prevent autoimmune diseases. Materials and Methods: In this study, to reduce the induction of tolerance due to PDL-1 binding to PD-1, the PD-1 gene was destroyed in PBMCs by the means of CRISPR-Cas9 and dual-transfection of two plasmids containing the Cas 9 gene and two different sgRNAs specific to two region of PD-1 gene in order to produce a deletion mutation. Six different sgRNA were designed and cloned in PX-458 plasmid vector, and PBMCs were transfected using lipofectamine 2000 and electroporation. Indels were evaluated by gel electrophoresis and Sanger sequencing. Results: We showed the PD-1 gene in PBMCs was knocked out successfully by CRISPR-Cas9 and dualtransfection of two sgRNAs. The minimum interval between the two sgRNAs was 448 nucleotides. Conclusion: The results of this research demonstrated that the use of dual-transfection of CRISPRCas9 sgRNA is a suitable method to knock out the PD-1 gene and prevention of inducing tolerance in PBMCs. [ABSTRACT FROM AUTHOR]

Idiopathic CD4 T cell lymphocytopenia (ICL) is a rare entity characterized by CD4 T cell count of <300 cells/mm3 along with opportunistic infection for which T cell marker expression remains to be fully explored. We report an ICL case for which T lymphocyte phenotype and its costimulatory molecules expression was analyzed both ex vivo and after overnight stimulation through CD3/CD28. The ICL patient was compared to five healthy controls. We observed higher expression of inhibitory molecules PD-1/PDL-1 and CTLA-4 on CD4 T cells and increased regulatory T cells in ICL, along with high activation and low proliferation of CD4 T cells. The alteration in the expression of both the costimulatory pathway and the apoptotic pathway might participate to down-regulate both CD4 T cell functions and numbers observed in ICL. [ABSTRACT FROM AUTHOR]

Traditionally, lung cancer has been treated as an immune-resistant disease with platinum-based chemotherapy serving as the first-line treatment for metastatic disease. The efficacy of immunotherapy has been established for patients with advanced lung cancer in clinical trials, and it has since become the standard of care for patients without targetable mutations, with or without chemotherapy. Previously, lung cancer patients experienced limited responses to immune-based therapy. As clinical trials continued to explore immunotherapy options with checkpoint inhibitors, results showed that immune therapies can create durable responses with manageable toxicities. Patients with advanced non-small cell lung cancer (NSCLC) can experience improved survival when administered immunotherapy over chemotherapy. The first successful immunotherapy treatments developed exploit programmed death 1/programmed death ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), immune checkpoint pathways. Combination therapies of PD-1/PD-L1 inhibitors and chemotherapy or PD-1/PD-L1 and CTLA-4 checkpoint pathway inhibitors have also demonstrated improved outcomes for patients with NSCLC. Combination therapy with PD-1 or PD-L1 therapy and chemotherapy has shown benefit for small cell lung cancer patients as well. As immunotherapy changes the treatment paradigm of lung cancer, researchers continue to investigate different combinations, timing, duration, and biomarkers to better understand and improve the efficacy of immune-based therapy for patients with lung cancer. [ABSTRACT FROM AUTHOR]

Stage III non-small cell lung cancer is a border line stage between localized and metastatic disease. PDL-1 is gaining an important role in the therapeutic arsenal of lung cancer, the most frequent cancer worldwide. We report for the first time a negativation of PDL-1 status in 2 cases of stage IIIA NSCLC with conversion to operable disease after using immunotherapy. The first patient was a 59-year old female diagnosed incidentally to have stage IIIA inoperable NSCLC that was treated with combination chemo-immunotherapy, and converted to operable disease with a negative PD-L1 in the postoperative setting. The second case is that of a 56-year old male that also had an inoperable stage IIIA NSCLC treated with chemotherapy first line followed by pembrolizumab at progression, then operated after surgical conversion, with negative PD-L1 postoperatively. In front of these findings, further work should be done to elucidate if the reverse of the PDL-1 status and the conversion to operability were due to the use of immunotherapy or to an incidental finding. If confirmed, it may have a therapeutic impact. [ABSTRACT FROM AUTHOR]

Background: colorectal cancer (CRC) is a major cause of cancer-related death worldwide. In recent years, targeting the programed cell death (PD-1)/ programed cell death-1 ligand (PD-L1) immune checkpoint signaling has been tested as a novel promising treatment strategy in several tumors. Aim of the work: the present study aimed to examine expression of PD-L1 and CD 8+ T cells in CRC and to evaluate the relationship between their expressions and the different clinicopathological features. Material and methods: expression of PD-L1 in tumor cells (TC) as well as in tumor infiltrating immune cells (TIMC) was separately evaluated in 85 cases of CRC by the immunohistochemistry, in addition, CD8+ T cell count was assessed. Results: 12.9 % of cases showed PD-L1 expression in TC while, 28.2% showed PD-L1expression in TIMC. PD-L1 expression in TC was significantly associated with higher tumor grade (P =0.001), lymph node metastasis (LNM) (P =0.006) and lymphovascular invasion (LVI) (P > 0.001). On the other hand, PDL-1 expression in TIMC was significantly associated with low tumor grade (P=0.016), negative LVI (P = 0.004), high tumor infiltrating lymphocytes (TILs) count (P <0.0001), as well as high CD8+ T cells count (P = 0.002). High intra CD8-positive T cells was significantly associated with absence of LNM (P =0.013) and negative LVI (P =0.035). Conclusion: these findings indicated that expression of PD-L1 can be used as a new biomarker to predict the prognosis of colon cancer and may provide a clue for immunotherapy in the adjuvant treatment of CRC patients. [ABSTRACT FROM AUTHOR]

Abstract The most common and lethal type of intracranial tumors include the astrocytomas. Grade IV astrocytoma or Glioblastoma (GBM) is highly aggressive and treatment-refractory with a median survival of only 14 to 16 months. Molecular profiling of GBMs reveals a high degree of intra- and inter-tumoral heterogeneity, and hence it is important to understand the important signalling axes that get deregulated in different GBM subtypes to provide effective tailor-made therapies. In this study, we have carried out extensive analysis of Reverse Phase Protein Array (RPPA) data from TCGA cohort to develop protein signatures that define glioma grades or subtypes. The protein signatures that distinguished Grade II or III from GBM had largely overlapped, and pathway analysis revealed the positive enrichment of extracellular matrix proteins (ECM), MYC pathway, uPAR pathway and G2/M checkpoint genes in GBM. We also identified protein signatures for GBMs with genetic alterations (IDH mutation, p53 mutation, EGFR amplification or mutation, CDKN2A/CDKN2B deletion, and PTEN mutation) that occur at high frequency. G-CIMP positive GBM-specific protein signature showed a large similarity with IDH1-mutant protein signature, thus signifying the importance of IDH1 mutation driving the G-CIMP. Gene expression subtype analysis revealed an association of specific proteins to classical (EGFR and phosphor variants), mesenchymal (SERPINE1, TAZ, and Myosin-IIa_pS1943), neural (TUBA1B), and proneural (GSK3_pS9) types. Univariate Cox regression analysis identified several proteins showing significant correlation with GBM survival. Multivariate analysis revealed that IGFBP2 and RICTOR_pT1135 are independent predictors of survival. Overall, our analyses reveal that specific proteins are regulated in different glioma subtypes underscoring the importance of diverse signalling axes playing important role in the pathogenesis of glioma tumors. Highlights • Extracellular matrix proteins (ECM), MYC pathway, uPAR pathway and G2/M checkpoint genes were positively enriched in GBM. • We identified protein signatures for GBMs with genetic alterations that occur at high frequency. • We identified association of proteins to specific gene expression suubtype. • IGFBP2 and RICTOR (pT1135) were independent predictors of survival in GBM. • PDL-1, SYK, HER3 and S6 (pS244/240) were found to be poor prognosticators in CL, MES, NL and PN subtypes respectively. [ABSTRACT FROM AUTHOR]

Recent experimental and genetic studies have implicated the role of programmed cell death protein 1 (PD-1), programmed cell death protein-ligand 1 (PDL-1), and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) in the pathogenesis of medium and large vessel vasculitis. This study sought to evaluate the occurrence and nature of vasculitis associated with cancer treatment using immune checkpoint inhibition (anti-PD-1, anti-PDL-1, and anti-CTLA4). A systematic review of the medical literature was conducted by searching all available clinical data up to February 2018 in several databases and search engines including Cochrane Library, Embase, Google Scholar, Medline, Scopus, Web of Science, and Clinicaltrials.gov. Searches included the following FDA-approved anti-PD1 (nivolumab and pembrolizumab), anti-PDL1 (atezolizumab, avelumab, and durvalumab), and anti-CTLA4 (ipilimumab). The vasculitis cases were compiled and classified based on the 2012 revised Chapel Hill Consensus Conference nomenclature. The clinical feature of the vasculitis cases and their relationship to immune checkpoint inhibition was assessed. There were 53 cases of vasculitis of which 20 were confirmed. The main reported type of vasculitis was large vessel vasculitis and vasculitis of the central and peripheral nervous system. All cases resolved with either holding the immune checkpoint inhibitors and/or administering glucocorticoids. No death related to vasculitis was reported. Vasculitis, namely large vessel and vasculitis of the nervous system, is associated with immune checkpoint inhibition. Results of this study add to the growing evidence regarding the relationship between immune checkpoints and vasculitis and suggest that the pathway may be a therapeutic target. [ABSTRACT FROM AUTHOR]

Objective The role of mismatch repair (MMR) deficiency in ovarian cancer (OC) pathogenesis and its association with other clinicopathologic features, such as microsatellite instability (MSI) and expression of checkpoint proteins, remain largely elusive. Methods We performed Immunohistochemistry (IHC) for MLH1, MSH2, MSH6 and PMS2 on full-section slides from 419 OCs to assess the MMR status. The clinical relevance of MMR deficiency was analyzed in combination with clinical data. The MSI status (by MSI assay) and expression of CD3, CD8, PD-1 and PD-L1 (by IHC) were compared in OCs with different MMR status. Results We found that 2.6% OCs were MMR-negative, 4.3% OCs were MMR-low, and 63.6% of MMR-negative OCs were of endometrioid subtype. A significantly higher proportion of MMR-negative OCs were diagnosed at stage I or II compared to MMR-proficient OCs (p = 0.0041). MSI was observed in all tested MMR-negative OCs, 14.3% of tested MMR-low OCs and 3.2% of tested MMR-proficient OCs. In addition, MMR-negative OCs had better progression free survival compared to MMR-proficient and MMR-low OCs (p = 0.0046). Furthermore, the majority of OCs were PD-1-positive in intratumoral lymphocytes regardless of MMR status; while MMR-negative OCs exhibited significantly increased CD3+ and CD8+ tumor-infiltrating lymphocytes, and PD-L1+ intratumoral immune cells compared to MMR-proficient OCs. Conclusion Our data suggests that MMR deficient OC is a unique molecular subgroup, characterized by early stage of diagnosis, MSI phenotype, and increased tumor-infiltrating lymphocytes. These patients may be good candidates for anti-PD-1/PD-L1 therapy. [ABSTRACT FROM AUTHOR]

Mounting evidences are supporting a key role of distinct gut bacteria in the occurrence and progression of intestinal and extra-intestinal tumors. More importantly, it has been recently demonstrated that some gut bacteria strains synergize with largely-used anticancer drugs as alkylating or immune checkpoint blockade agents thus optimizing the immune response against multiple solid cancers. However, the exact role played by each gut bacterium in cancer occurrence and response to therapy is still in its infancy; and the current knowledge, although exciting, still needs to be transferred from mice models to human beings. Here, the advances in the understanding of how gut microbes and immune response shape each other in a cancer context are reviewed together with the implications of these finding for future antitumor therapy. Herein, the most important bacteria strains, able to boost the immune response triggered by anticancer drugs, together with their mechanism of action, whenever known, have been surveyed. It is reasonable to think that cocktails of beneficial bacteria together with an ad hoc diet or food supplements may be used as novel anticancer adjuvant agents in future therapeutic regimens. [ABSTRACT FROM AUTHOR]

For the management of patients with recurrent or advanced NSCLC, several parameters should be taken into consideration, such as; the histological type, the presence of biomarkers, age, functional status, comorbidities and patient preferences. The optimal management scenario for these patients should be within a unit of thoracic tumors with a multidisciplinary discussion that allows recommending additional diagnostic tests and evaluating the best treatment to follow[1]. All patients with clinical stages IV or recurrent disease, and with adequate functional status (ECOG 0-2, of the acronym "Eastern Cooperative Oncology Group"), should receive palliative systemic therapy with the aim of improving overall survival (SG), the quality of life and control the symptoms associated with the disease (Table 1). The choice of the first and subsequent lines of systemic treatment will depend on: the functional state of the patient, the availability of molecular tests and targeted therapies[1]. [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages (TAMs) play an important role in remodeling the tumor microenvironment (TME), which promotes tumor growth, immunosuppression and angiogenesis. Because of the high plasticity of macrophages and the extremely complex tumor microenvironment, the mechanism of TAMs in cancer progression is still largely unknown. In this study, we found that xCT (SLC7A11) was overexpressed in lung cancer-associated macrophages. Higher xCT in TAMs was associated with poor prognosis and was an independent predictive factor in lung cancer. In addition, lung cancer growth and progression was inhibited in xCT knockout mice, especially macrophage-specific xCT knockout mice. We also found that the deletion of macrophage xCT inhibited AKT/STAT6 signaling activation and reduced M2-type polarization of TAMs. Macrophage xCT deletion recruited more CD8+ T cells and activated the lung cancer cell-mediated and IFN-γ-induced JAK/STAT1 axis and increased the expression of its target genes, including CXCL10 and CD274. The combination of macrophage xCT deletion and anti-PDL1 antibody achieved better tumor inhibition. Finally, combining the xCT inhibitor erastin with an anti-PDL1 antibody was more potent in inhibiting lung cancer progression. Therefore, suppression of xCT may overcome resistance to cancer immunotherapy. • High TAM-derived xCT was an independent risk factor in lung cancer; xCT deletion inhibited the progression of lung cancer. • xCT in macrophages mediated AKT/STAT6 signaling and M2-type polarization while also influenced IFN-γ-induced JAK/STAT1 axis. • The combination of macrophage xCT deletion and anti-PDL1 therapy showed a better tumor inhibition effect. • The xCT inhibitor erastin functioned as an anti-tumor agent, especially combined with anti-PDL1 therapy. [ABSTRACT FROM AUTHOR]

We investigated whether hypoxia-induced activation of Hh signaling contributes to PDL-1 expression in cancer and whether it affects the anti-tumor function of activated lymphocytes. Hypoxia augmented PDL-1 expression and inhibition of Hh signaling reduced PDL-1 expression under hypoxia. When activated lymphocytes were cocultured with cancers treated with a Hh inhibitor, activated lymphocyte cell numbers increased under hypoxia. In contrast, this increase was abrogated when cancer cells were treated with a PDL-1 neutralizing antibody. These results suggest that Hh signaling is one of regulatory pathways of PDL-1 expression under hypoxia and that inhibiting Hh signaling may induce lymphocyte anti-tumor activity. [ABSTRACT FROM AUTHOR]

Surgery is still the best treatment option of lung cancer but only one third of patients are operable and prognosis remains mediocre in operated patients, with the exception of initial stages. Medical treatment is fast moving toward new frontiers. New insights in the biology of cancer development led to discovery of new drugs, which are more effective as compared to conventional platinum based chemotherapy. A new approach to immunotherapy based on immune-check point represents a remarkable innovation in lung cancer treatment. Initial trials with anti PD-1 antibodies in metastatic patients provided results never observed with previously known drug categories. Several key question need to be answered to identify patients most likely to respond to anti PD-1/anti PD-L1 treatments, to assess the role of combined treatment modalities including immune check point receptor block (associations with surgery, chemotherapy, ITKs), and to boost host immune response, possibly by lowering his systemic inflammation and improving nutritional status. [ABSTRACT FROM AUTHOR]

FKBP51 (gene FKBP5) is an immunophilin capable of immunosuppression expressed in melanoma and lymphocytes. We found increased levels of a spliced FKBP5 variant in the PBMCs of 124 patients with melanoma. This variant encodes for an unknown isoform ( FKBP51s). We hypothesized that FKBP51s resulted from tumour interaction with immune cells, through PDL-1/ PD-1. To address this issue, we performed melanoma/ PBMC cocultures. Furthermore, the immunohistochemistry of 76 melanoma specimens served to investigate whether FKBP51s stained tumour infiltrating lymphocytes. Our results showed that PBMCs expressed FKBP51s when cocultured with melanoma. Tumour PDL-1 knockdown or anti- PD-1 reduced FKBP51s expression in cocultured PBMCs. IHC showed a strong FKBP51s signal in tumour infiltrating lymphocytes, and lymphocytes of the invasion front of the tumour, along with melanoma PDL-1 expression. When overexpressed in melanoma, FKBP51s facilitated PDL-1 expression on the cell surface. In conclusion, our study shows that FKBP51s marks the PBMCs of patients with melanoma and is exploited by the tumour to immunomodulate through PDL-1. [ABSTRACT FROM AUTHOR]

The vast genetic alterations characteristic of tumours produce a number of tumour antigens that enable the immune system to differentiate tumour cells from normal cells. Counter to this, tumour cells have developed mechanisms by which to evade host immunity in their constant quest for growth and survival. Tumour-associated antigens (TAAs) are one of the fundamental triggers of the immune response. They are important because they activate, via major histocompatibility complex (MHC), the T cell response, an important line of defense against tumourigenesis. However, the persistence of tumours despite host immunity implies that tumour cells develop immune avoidance. An example of this is the up-regulation of inhibitory immune checkpoint proteins, by tumours, which induces a form of self-tolerance. The majority of monoclonal antibodies in clinical practice have been developed to target tumour-specific antigens. More recently there has been research in the down-regulation of immune checkpoint proteins as a way of increasing anti-tumour immunity. [ABSTRACT FROM AUTHOR]

Abstract: NKT cells are innate lymphocytes that can recognize self or foreign lipids presented by CD1d molecules. NKT cells have been shown to inhibit the development of autoimmunity in murine model systems, however, the pathways by which they foster immune tolerance remain poorly understood. Here we show that autoreactive human NKT cells stimulate monocytes to differentiate into myeloid APCs that have a regulatory phenotype characterized by poor conjugate formation with T cells. The NKT cell instructed myeloid APCs show elevated expression of the inhibitory ligand PD-L2, and blocking PD-L1 and PD-L2 during interactions of the APCs with T cells results in improved cluster formation and significantly increased T cell proliferative responses. The elevated expression of PD-L molecules on NKT-instructed APCs appears to result from exposure to extracellular ATP that is produced during NKT-monocyte interactions, and blocking purinergic signaling during monocyte differentiation results in APCs that form clusters with T cells and stimulate their proliferation. Finally, we show that human monocytes and NKT cells that are injected into immunodeficient mice co-localize together in spleen and liver, and after 3 days in vivo in the presence of NKT cells a fraction of the myeloid cells have upregulated markers associated with differentiation into professional APCs. These results suggest that autoreactive human NKT cells may promote tolerance by inducing the differentiation of regulatory myeloid APCs that limit T cell proliferation through expression of PD-L molecules. [Copyright &y& Elsevier]

Abstract: Characterization of CTLA-4, PD-1 and PDL-1 genes from swamp and riverine type water buffaloes was done by molecular cloning, sequencing and phylogenetic analysis. The cloned cDNA of CTLA-4, PD-1 and PDL-1 contained an open reading frame of 666, 849 and 870 nucleotides, encoding a polypeptide of 221, 282 and 298 amino acids, respectively. Nucleotide sequence homology of both CTLA-4 and PDL-1 had 99.8% in swamp and riverine type, which gives the identical polypeptide. Meanwhile, PD-1 genes of swamp and riverine type water buffaloes had 99.2% of homology in nucleotide sequence, which has substitution of two amino acid residues. The hexapeptide motif, phosphatidylinositol 3′-kinase and potential glycosylation sites were conserved within the tribe Bovinae. Phylogenetic analysis confirmed the degree of relationship between the bubaline species and justify the distinctness of each breeds by the bootstrap value generated. [Copyright &y& Elsevier]

Abstract: The development of novel in vitro methods to assess risks of allergic sensitization are essential in reducing animal testing whilst maintaining consumer safety. The main research objectives of this study were to identify novel biomarkers to assess the sensitization predictability of chemicals. Phenotypic and cytokine responses of moDCs and MUTZ-3 cells were investigated following application of contact sensitizers; dinitrochlorobenzene (DNCB), cinnamaldehyde (Cin), eugenol (E), isoeugenol (IE), P-phenylenediamine (PPD) and non-sensitizers; salicyclic acid (SA) and sodium lauryl sulphate (SLS). CD86 was up-regulated on MUTZ-3 cells in response to DNCB, Cin and PPD, however, moDCs only modulated CD86 in response to DNCB and E. PDL-1 (Programmed death receptor ligand-1) proved a promising sensitization biomarker in MUTZ-3 cells where up-regulation occurred in response to DNCB, Cin, IE and PPD. Additionally, moDC-expressed PDL-1 was modulated in response to Cin, IE and E thus demonstrating improved sensitizer predictability when compared with CD86. MCP-1 and RANTES were identified as biomarkers of DNCB exposure but MCP-1 did not show any change in expression above controls for the other sensitizers investigated. However, RANTES was increased in MUTZ-3 cells by both DNCB and Cin. Our findings highlight novel biomarkers which, in MUTZ-3 cells, could be taken forward within a multiple biomarker in vitro assay ensuring strong and reliable predictability. [ABSTRACT FROM AUTHOR]

Abstract: Immunotherapy is a promising new treatment for patients suffering from glioma, in particular glioblastoma multiforme (GBM). However, tumour cells use different mechanisms to escape the immune responses induced by the treatment. As many other tumours, gliomas express or secrete several immunosuppressive molecules that regulate immune cell functions. In this study, we first analysed FasL, HLA-G, IDO, PDL-1 and TGF-β1, -β2 and -β3 expression by transcriptomic microarray analysis in a series of 20 GBM samples and found respectively 15%, 60%, 85%, 30%, 70%, 80% and 35% of positive specimens. mRNA expression was then confirmed in 10 GBM primary cell lines and 2 immortalised cell lines U251 and U87MG. Furthermore, the protein expression of PDL-1, IDO activity and TGF-β2 secretion were found on most of the untreated GBM primary cell lines. Remarkably, treatment with IFN-γ increased the PDL-1 cell surface expression and the IDO activity, but reduced the TGF-β2 secretion of GBM cell lines. We finally analysed the immunosuppressive effects of IDO, PDL-1 and TGF-β1-3 by measuring IFN-γ production and cell cytotoxicity activity of tumour antigen-specific T cells. PDL-1 partially affected the IFN-γ production of antigen-specific T cells in response to GBM primary cell lines, and IDO inhibited lymphocyte proliferation induced by lectins. None of these molecules directly affected the T cell cytotoxicity function. Due to the functional role of PDL-1 and IDO molecules expressed by GBM cells, one could expect that blocking these molecules in the immunotherapy strategies would reinforce the efficiency of these treatments of GBM patients. [ABSTRACT FROM AUTHOR]

Immunotherapy such as nivolumab is a new promising therapeutic option for advanced stage non small cell lung cancer (NSCLC). Due to the interference with the immune system previously unknown side effects are observed both in clinical studies and experience. Autoimmune phenomena effecting skin, gastrointestinal tract, endocrine glands, kidney and lung have been described. Up to now there is only limited information regarding potential cardiac side effects. We present a case of symptomatic drug induced myocarditis after nine cycles of nivolumab in a patient with efficient anticancer response. [ABSTRACT FROM AUTHOR]

• High expression of ESCO2 are associated with poor prognosis. • Hypomethylation of ESCO2 is associated with poor prognosis in LGG patients. • ESCO2 can be used as a prognostic indicator of LGG. • ESCO2 provides a new therapeutic target for the treatment of LGG. The establishment of sister chromatid cohesion N-acetyltransferase 2 (ESCO2) has an important regulatory effect on cell proliferation and division, which is closely related to the malignant process of glioma cells. Therefore, this study attempts to provide a target for biologically targeted therapy for low-grade glioma (LGG) by demonstrating the regulatory effect of ESCO2 during the pathological process of LGG. First, the 1064 samples of LGG transcriptomic data and corresponding clinicopathological information obtained from various databases were included in the study. Second, the chi-squared test showed that the expression of ESCO2 was associated with the malignant characteristics of LGG (recurrence and grade), and Kaplan Meier and multivariate analysis suggested that ESCO2 was an independent risk factor, resulting in a significant reduction in the overall duration of survival of patients. Third, co-expression analysis showed that the level of mRNA expression of ESCO2 was negatively regulated by multiple methylation sites (cg04108328, cg12564175, and cg26534677), and the hypermethylation status of cg12564175 could prolong the overall survival of patients. Fourth, the Tumor Immune Estimation Resource (TIMER) database shows that ESCO2 can have a positive regulatory relationship with six different immune cells, such as CD8 + T cells and macrophages, and a positive expression relationship with PD-1 and PD-L1. Finally, Gene Set Enrichment Analysis (GSEA) showed that ESCO2 may play a carcinogenic role by affecting cell replication and DNA repair. In summary, this study confirmed the carcinogenic effect of ESCO2 on LGG for the first time. It is speculated that both the mRNA of ESCO2 and its methylation site (cg12564175) can be useful biological targets for molecular targeted therapy of LGG. [ABSTRACT FROM AUTHOR]

Checkpoint inhibitors have revolutionized treatments in modern oncology, including many conditions previously relegated to palliative therapies only. However, emerging recognition of checkpoint inhibitor-related adverse events has complicated the status of checkpoint inhibitor-related therapies. This review article discusses gastrointestinal adverse events as a result of checkpoint inhibitor therapy, as well as limitations of current guidelines, thus providing recommendations for guideline revision and future study direction. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein (PD-1), and its ligand PDL-1, are finding increasing application in the treatment of malignant neoplasms. The widespread clinical use of these drugs, however, resulted in the discovery of side effects. The occurrence of celiac disease (CD) after ICIs therapy has been reported in the literature, but its incidence remains unknown and the role of ICIs in its onset is not yet clear. In this review, we examine the published data on this topic in order to better understand and define this entity from a histological point of view. We performed an electronic literature search to identify original reports in which CD or pathological CD-like conditions were documented histologically in patients treated with ICIs. We identified ten papers. A total of twenty-five patients were included in these publications, eleven of them receiving a serologic and histological diagnosis of CD, and four a histological diagnosis of CD-like conditions, in which pathogenesis appears to be multifactorial. ICIs can cause a CD-like enteropathy and biopsies with clinical integration are crucial to diagnose this condition. CD rarely has been observed during treatment with ICIs and its morphological aspects are similar to ICIs-CD enteropathy. Moreover, the onset of ICIs-CD may have a distinct immune mechanism compared to classical CD. Thus, the pathologists must make a histological diagnosis of CD with caution and only in adequate clinical and serological context. [ABSTRACT FROM AUTHOR]

Abstract: The programmed death (PD)-1 interacts with its ligand (PDL-1) delivering a negative signal to T cells. During human immunodeficiency virus (HIV)-1 infection PD-1 and PDL-1 expressions are increased. Here we show that monocytes and CCR5+ T cells of HIV-uninfected donors upregulated PDL-1 upon in vitro exposure to HIV. HIV-induced PDL-1 required interferon (IFN)-α, but not IFN-γ, production. Inhibition of endocytosis, required for HIV-induced IFN-α production, prevented PDL-1 upregulation. IFN-α-inducing Toll-like receptor (TLR) agonists increased PDL-1 on monocytes and CCR5+ T cells. CD80 and CD86 were also increased on monocytes and CCR5+ T cells after HIV exposure, but only CD80 was IFN-α-dependent. IFN-α-receptor subunit 2 (IFNAR2), was expressed only by CCR5+ T cells and monocytes, explaining why these leukocytes responded to HIV-induced IFN-α. Finally, T cell proliferation was improved by PDL-1 blockade in HIV-treated PBMC. In the setting of HIV infection, IFN-α may negatively affect T cell responses by inducing PDL-1. [Copyright &y& Elsevier]

Simple Summary: Ovarian cancer has remained the leading cause of death among gynecologic malignancies. The current standard of treatment, in most cases, is a combination of surgery and chemotherapy, based on platinum agents and taxanes. Despite the increasing usage of newer drug groups, such as bevacizumab and PARP inhibitors, and the expansion of patient groups for these drugs, ovarian cancer is characterized by recurrences, particularly in the form of peritoneal implants. This review focuses on immunotherapy for ovarian cancer. It considers the current state of knowledge in areas such as cancer vaccines, adoptive cell therapy, CAR-T therapy, and anti-CTLA-4 monotherapy. The paper specifically considers PD-1/PDL-1 as drug targets. Anti-PD-1/PD-L1 monotherapy, and anti-PD-1/PD-L1 immunotherapy in combination with other agents, are analyzed. Ovarian cancer is one of the most fatal cancers in women worldwide. Cytoreductive surgery combined with platinum-based chemotherapy has been the current first-line treatment standard. Nevertheless, ovarian cancer appears to have a high recurrence rate and mortality. Immunological processes play a significant role in tumorigenesis. The production of ligands for checkpoint receptors can be a very effective, and undesirable, immunosuppressive mechanism for cancers. The CTLA-4 protein, as well as the PD-1 receptor and its PD-L1 ligand, are among the better-known components of the control points. The aim of this paper was to review current research on immunotherapy in the treatment of ovarian cancer. The authors specifically considered immune checkpoints molecules such as PD-1/PDL-1 as targets for immunotherapy. We found that immune checkpoint-inhibitor therapy does not have an improved prognosis in ovarian cancer; although early trials showed that a combination of anti-PD-1/PD-L1 therapy with targeted therapy might have the potential to improve responses and outcomes in selected patients. However, we must wait for the final results of the trials. It seems important to identify a group of patients who could benefit significantly from treatment with immune checkpoints inhibitors. However, despite numerous trials, ICIs have not become part of routine clinical practice for the treatment of ovarian cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic cancer remains one of the most challenging malignancies to treat with standard approaches. Emerging treatment approaches incorporating innovative surgical techniques and novel systemic therapies may help to improve outcomes for pancreas cancer patients. Although immunotherapy has proven to be less effective for the treatment of pancreas cancer relative to more immunogenic tumor types, multiple immune system stimulating agents are under active investigation for pancreatic ductal adenocarcinoma, either alone or in combination with other therapeutic agents. The tumor microenvironment of pancreatic cancer is also an attractive therapeutic target given that it is believed to be highly immunosuppressive and encapsulated by a dense stroma. This review article aims to summarize pre-clinical and clinical studies, including ongoing clinical trials, which attempt to incorporate novel treatment approaches for pancreas cancer. Emerging treatment approaches may help to significantly improve outcomes for this tough to treat disease. Pancreatic Ductal Adenocarcinoma (PDAC) is one of the deadliest malignancies among all cancers. Despite curative intent, surgery and the use of standard cytotoxic chemotherapy and radiation therapy, PDAC remains treatment-resistant. In recent years, more contemporary treatment modalities such as immunotherapy via checkpoint inhibition have shown some promise in many other malignancies, yet PDAC still eludes an effective curative treatment. In investigating these phenomena, research has suggested that the significant desmoplastic and adaptive tumor microenvironment (TME) of PDAC promote the proliferation of immunosuppressive cells and act as major obstacles to treatment efficacy. In this review, we explore challenges associated with the treatment of PDAC, including its unique immunosuppressive TME. This review examines the role of surgery in PDAC, recent advances in surgical approaches and surgical optimization. We further focus on advances in immunotherapeutic approaches, including checkpoint inhibition, CD40 agonists, and discuss promising immune-based future strategies, such as therapeutic neoantigen cancer vaccines as means of overcoming the resistance mechanisms which underly the dense stroma and immune milieu of PDAC. We also explore unique signaling, TME and stromal targeting via novel small molecule inhibitors, which target KRAS, FAK, CCR2/CCR5, CXCR4, PARP and cancer-associated fibroblasts. This review also explores the most promising strategy for advancement in treatment of pancreatic cancer by reviewing contemporary combinatorial approaches in efforts to overcome the treatment refractory nature of PDAC. [ABSTRACT FROM AUTHOR]