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BACKGROUND: Immunotherapy-based combinations have emerged as standard therapies for patients with metastatic renal cell carcinoma (mRCC). Pembrolizumab, a PD-1 inhibitor, combined with epacadostat, an indoleamine 2,3-deoxygenase 1 selective inhibitor, demonstrated promising antitumor activity in a phase 1 study in advanced solid tumors, including mRCC. METHODS: KEYNOTE-679/ECHO-302 was a randomized, open-label, parallel-group, multicenter, phase 3 study (NCT03260894) that compared pembrolizumab plus epacadostat with sunitinib or pazopanib as first-line treatment for mRCC. Eligible patients had histologically confirmed locally advanced or metastatic clear cell RCC and had not received systemic therapy. Patients were randomly assigned 1:1 to pembrolizumab 200 mg IV every 3 weeks plus epacadostat 100 mg orally twice daily versus sunitinib 50 mg orally once daily (4 weeks on treatment followed by 2 weeks off treatment) or pazopanib 800 mg orally once daily. Original dual primary end points were progression-free survival and overall survival. Enrollment was stopped when a phase 3 study in melanoma of pembrolizumab plus epacadostat compared with pembrolizumab monotherapy did not meet its primary end point. This protocol was amended, and primary end point was changed to investigator-assessed objective response rate (ORR) per RECIST 1.1. RESULTS: One-hundred-twenty-nine patients were randomly assigned to receive pembrolizumab plus epacadostat (n = 64) or sunitinib/pazopanib (n = 65). Median (range) follow-up, defined as time from randomization to data cutoff, was 10.3 months (2.2-14.3) and 10.3 months (2.7-13.8) in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. ORRs were similar between pembrolizumab plus epacadostat (31.3% [95% CI 20.2-44.1] and sunitinib/pazopanib (29.2% [18.6-41.8]). Grade 3-5 treatment-related adverse events occurred in 34.4% and 42.9% of patients in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. One patient in the sunitinib/pazopanib arm died of septic shock (not treatment-related). Circulating kynurenine levels decreased in the pembrolizumab plus epacadostat arm, but not to levels observed in healthy subjects. CONCLUSIONS: ORRs were similar between pembrolizumab plus epacadostat and sunitinib/pazopanib as first-line treatment in patients with mRCC. Safety and tolerability appeared similar between treatment arms; no new safety concerns were identified. Antitumor responses observed in patients with RCC receiving pembrolizumab plus epacadostat may be driven primarily by pembrolizumab. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; NCT03260894 .

ObjectivesSome drugs that augment cell-intrinsic defenses or modulate cell death/survival pathways have been reported to selectively kill cells infected with HIV or Simian Immunodeficiency Virus (SIV), but comparative studies are lacking. We hypothesized that these drugs may differ in their ability to kill cells infected with intact and defective proviruses.DesignTo investigate this hypothesis, drugs were tested ex vivo on peripheral blood mononuclear cells (PBMC) from nine antiretroviral therapy (ART)-suppressed individuals.MethodsWe tested drugs currently in clinical use or human trials, including auranofin (p53 modulator), interferon alpha2A, interferon gamma, acitretin (RIG-I inducer), GS-9620/vesatolimod (TLR7 agonist), nivolumab (PD-1 blocker), obatoclax (Bcl-2 inhibitor), birinapant [inhibitor of apoptosis proteins (IAP) inhibitor], bortezomib (proteasome inhibitor), and INK128/sapanisertib [mammalian target of rapamycin mTOR] [c]1/2 inhibitor). After 6 days of treatment, we measured cell counts/viabilities and quantified levels of total, intact, and defective HIV DNA by droplet digital PCR (Intact Proviral DNA Assay).ResultsObatoclax reduced intact HIV DNA [median = 27-30% of dimethyl sulfoxide control (DMSO)] but not defective or total HIV DNA. Other drugs showed no statistically significant effects.ConclusionObatoclax and other Bcl-2 inhibitors deserve further study in combination therapies aimed at reducing the intact HIV reservoir in order to achieve a functional cure and/or reduce HIV-associated immune activation.

Summary Following success in cancer immunotherapy, immune checkpoint blockade is emerging as an exciting potential treatment for some infectious diseases, specifically two chronic viral infections, HIV and hepatitis B. Here, we will discuss the function of immune checkpoints, their role in infectious disease pathology, and the ability of immune checkpoint blockade to reinvigorate the immune response. We focus on blockade of programmed cell death 1 (PD‐1) to induce durable immune‐mediated control of HIV, given that anti‐PD‐1 can restore function to exhausted HIV‐specific T cells and also reverse HIV latency, a long‐lived form of viral infection. We highlight several key studies and future directions of research in relation to anti‐PD‐1 and HIV persistence from our group, including the impact of immune checkpoint blockade on the establishment (AIDS, 2018, 32, 1491), maintenance (PLoS Pathog, 2016, 12, e1005761; J Infect Dis, 2017, 215, 911; Cell Rep Med, 2022, 3, 100766) and reversal of HIV latency (Nat Commun, 2019, 10, 814; J Immunol, 2020, 204, 1242), enhancement of HIV‐specific T cell function (J Immunol, 2022, 208, 54; iScience, 2023, 26, 108165), and investigating the effects of anti‐PD‐1 and anti‐CTLA‐4 in vivo in people with HIV on ART with cancer (Sci Transl Med, 2022, 14, eabl3836; AIDS, 2021, 35, 1631; Clin Infect Dis, 2021, 73, e1973). Our future work will focus on the impact of anti‐PD‐1 in vivo in people with HIV on ART without cancer and potential combinations of anti‐PD‐1 with other interventions, including therapeutic vaccines or antibodies and less toxic immune checkpoint blockers. [ABSTRACT FROM AUTHOR]

Lymphocyte activation gene 3 (LAG-3), also known as CD223, is an emerging immune checkpoint that follows PD-1 and CTLA-4. Several LAG-3 targeting inhibitors in clinical trials and the combination of relatlimab (anti-LAG-3) and nivolumab (anti-PD-1) have been approved for treating - unresectable or metastatic melanoma. Despite the encouraging clinical potential of LAG-3, the physiological function and mechanism of action in tumors are still not well understood. In this review, we systematically summarized the structure of LAG-3, ligands of LAG-3, cell-specific functions and signaling of LAG-3, and the current status of LAG-3 inhibitors under development. [ABSTRACT FROM AUTHOR]

Introduction: The role of zinc (Zn) in tumor development and immune modulation has always been paradoxical. This study redefines our understanding of the impact of Zn on cancer progression and therapeutic strategies. Methods: We investigated the effects of dietary Zn levels on tumor progression and immune responses. This included examining the impact of both high and deficient dietary Zn, as well as Zn chelation, on tumor growth and immune cell populations. Specifically, we analyzed the frequency of Foxp3+ regulatory T-cells (Tregs) and identified the role of FOXO1 in Zn-mediated effects on Tregs. Additionally, we explored the therapeutic potential of clioquinol (CQ) in enhancing α-PD-1 immunotherapy responses, particularly in melanoma. Results: Our findings show that high dietary Zn promotes tumor progression by fostering a protumorigenic environment mediated by T cells. Increased Zn intake was found to facilitate tumor progression by increasing Foxp3+ Treg frequency. In contrast, deficiency in dietary Zn and chelation of tissue Zn emerged as potent drivers of antitumor immunity. We pinpointed FOXO1 as the master regulator governing the influence of Zn on Tregs. Discussion: These results reveal a novel mechanistic insight into how Zn influences tumor progression and immune regulation. The identification of FOXO1 as a key regulator opens new avenues for understanding the role of Zn in cancer biology. Furthermore, we introduce a promising therapeutic approach by showing that administering clioquinol (CQ) significantly enhances α-PD-1 immunotherapy response, particularly in melanoma. These revelations transform our comprehension of the multifaceted role of Zn in tumorigenesis and immune regulation, highlighting innovative possibilities for cancer therapy. [ABSTRACT FROM AUTHOR]

Programmed death receptor-1 (PD-1) and its ligand, programmed death ligand-1 (PD-L1) are essential molecules that are key in modulating immune responses. PD-L1 is constitutively expressed on various immune cells, epithelial cells, and cancer cells, where it functions as a co-stimulatory molecule capable of impairing T-cell mediated immune responses. Upon binding to PD-1 on activated T-cells, the PD-1/PD-L1 interaction triggers signaling pathways that can induce T-cell apoptosis or anergy, thereby facilitating the immune escape of tumors. In urological cancers, including bladder cancer (BCa), renal cell carcinoma (RCC), and prostate cancer (PCa), the upregulation of PD-L1 has been demonstrated. It is linked to poor prognosis and enhanced tumor immune evasion. Recent studies have highlighted the significant role of the PD-1/PD-L1 axis in the immune escape mechanisms of urological cancers. The interaction between PD-L1 and PD-1 on T-cells further contributes to immunosuppression by inhibiting T-cell activation and proliferation. Clinical applications of PD-1/PD-L1 checkpoint inhibitors have shown promising efficacy in treating advanced urological cancers, significantly improving patient outcomes. However, resistance to these therapies, either intrinsic or acquired, remains a significant challenge. This review aims to provide a comprehensive overview of the role of the PD-1/PD-L1 signaling pathway in urological cancers. We summarize the regulatory mechanism underlying PD-1 and PD-L1 expression and activity, including genetic, epigenetic, post-transcriptional, and post-translational modifications. Additionally, we discuss current clinical research on PD-1/PD-L1 inhibitors, their therapeutic potential, and the challenges associated with resistance. Understanding these mechanisms is crucial for developing new strategies to overcome therapeutic limitations and enhance the efficacy of cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Lymphocyte activation gene (Lag)-3 is an inhibitory co-receptor and target of immune checkpoint inhibitor (ICI) therapy for cancer. The dynamic behavior of Lag-3 was analyzed at the immune synapse upon T-cell activation to elucidate the Lag-3 inhibitory mechanism. Lag-3 formed clusters and co-localized with T-cell receptor microcluster (TCR-MC) upon T-cell activation similar to PD-1. Lag-3 blocking antibodies (Abs) inhibited the co-localization between Lag-3 and TCR-MC without inhibiting Lag-3 cluster formation. Lag-3 also inhibited MHC-II-independent stimulation and Lag-3 Ab, which did not block MHC-II binding could still block Lag-3's inhibitory function, suggesting that the Lag-3 Ab blocks the Lag-3 inhibitory signal by dissociating the co-assembly of TCR-MC and Lag-3 clusters. Consistent with the combination benefit of PD-1 and Lag-3 Abs to augment T-cell responses, bispecific Lag-3/PD-1 antagonists effectively inhibited both cluster formation and co-localization of PD-1 and Lag-3 with TCR-MC. Therefore, Lag-3 inhibits T-cell activation at TCR-MC, and the target of Lag-3 ICI is to dissociate the co-localization of Lag-3 with TCR-MC. [ABSTRACT FROM AUTHOR]

The programmed cell death protein 1 (PD-1, CD279) is an important therapeutic target in many oncological diseases. This checkpoint protein inhibits T lymphocytes from attacking other cells in the body and thus blocking it improves the clearance of tumor cells by the immune system. While there are already multiple FDA-approved anti-PD-1 antibodies, including nivolumab (Opdivo® from Bristol-Myers Squibb) and pembrolizumab (Keytruda® from Merck), there are ongoing efforts to discover new and improved checkpoint inhibitor therapeutics. In this study, we present multiple anti-PD-1 antibody fragments that were derived computationally using protein diffusion and evaluated through our scalable, in silico pipeline. Here we present nine synthetic Fv structures that are suitable for further empirical testing of their anti-PD-1 activity due to desirable predicted binding performance. [ABSTRACT FROM AUTHOR]

Previous studies showed an association between single nucleotide gene variants (SNVs) of PD-1 and cancer susceptibility. We analyzed PD1.5 C > T and PD1.7 T > C SNVs to investigate their association with the risk of developing metastatic melanoma (MM). Utilizing a cohort of 125 MM patients treated with anti-PD-1 agents and 84 healthy controls, we examined genotype/allele frequencies through a modified Poisson regression model, adjusted for age and sex. Our findings indicate that the PD1.5 T allele is associated with a reduced risk of MM, showing a significantly lower risk in both codominant (RR = 0.56, 95%CL: 0.37–0.87) and dominant (RR = 0.73 95%CL: 0.59–0.90) models. Conversely, the PD1.7 C allele is linked to an increased risk of MM, with the C/C genotype exhibiting a higher risk in the codominant (RR = 1.65, 95%CL: 1.32–2.05) and allelic (RR = 1.23, 95%CL: 1.06–1.43) models. These results are consistent with previous meta-analyses on other cancer types, mainly highlighting the PD1.5 SNV’s potential role in promoting anti-tumor immunity through increased PD1-positive circulating effector T cell activity. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitor therapy can provide significant clinical benefit in patients with certain cancer types including melanoma; however, objective responses are only observed for a subset of patients. Mucosal melanoma is a rare melanoma subtype associated with a poor prognosis and, compared with cutaneous melanoma, is significantly less responsive to immune checkpoint inhibitors. Spontaneous canine tumours have emerged as valuable models to inform human cancer studies. In contrast to human melanoma, most canine melanomas are mucosal—an incidence that may be leveraged to better understand the subtype in humans. However, a more comprehensive understanding of the immune landscape of the canine disease is required. Here, we quantify tumour infiltrative T and myeloid cells in canine mucosal (n = 13) and cutaneous (n = 5) melanomas using immunohistochemical analysis of CD3 and MAC387 expression, respectively. Gene expression analysis using the Canine IO NanoString panel was also performed to identify genes and pathways associated with immune cell infiltration. T and myeloid cell densities were variable with geometric means of 158.7 cells/mm2 and 166.7 cells/mm2, respectively. Elevated T cell infiltration was associated with increased expression of cytolytic genes as well as genes encoding the coinhibitory checkpoint molecules PD‐1, CTLA‐4, TIM‐3 and TIGIT; whereas increased myeloid cell infiltration was associated with elevated expression of protumourigenic cytokines. These data provide a basic characterization of the tumour microenvironment of canine malignant melanoma and suggest that, like human melanoma, inherent variability in anti‐tumour T cell responses exists and that a subset of canine melanomas may respond better to immunomodulation. [ABSTRACT FROM AUTHOR]

Intracranial tumors present a significant therapeutic challenge due to their physiological location. Immunotherapy presents an attractive method for targeting these intracranial tumors due to relatively low toxicity and tumor specificity. Here we show that SCIB1, a TRP-2 and gp100 directed ImmunoBody® DNA vaccine, generates a strong TRP-2 specific immune response, as demonstrated by the high number of TRP2-specific IFNγ spots produced and the detection of a significant number of pentamer positive T cells in the spleen of vaccinated mice. Furthermore, vaccine-induced T cells were able to recognize and kill B16HHDII/DR1 cells after a short in vitro culture. Having found that glioblastoma multiforme (GBM) expresses significant levels of PD-L1 and IDO1, with PD-L1 correlating with poorer survival in patients with the mesenchymal subtype of GBM, we decided to combine SCIB1 ImmunoBody® with PD-1 immune checkpoint blockade to treat mice harboring intracranial tumors expressing TRP-2 and gp100. Time-to-death was significantly prolonged, and this correlated with increased CD4+ and CD8+ T cell infiltration in the tissue microenvironment (TME). However, in addition to PD-L1 and IDO, the GBM TME was found to contain a significant number of immunoregulatory T (Treg) cell-associated transcripts, and the presence of such cells is likely to significantly affect clinical outcome unless also tackled. [ABSTRACT FROM AUTHOR]

Purpose: To compare the risk of immune-associated pneumonitis between PD-1 and PD-L1 inhibitors, the meta-analysis was designed. Method: The difference in risk of immune-associated pneumonitis between PD-1 and PD-L1 inhibitors was assessed by two different meta-analysis methods, the Mirror-pairing and the PRISMA guidelines. Results: A total of eighty-eight reports were used for meta-analysis, while thirty-two studies were used for the Mirror-pairing. Both PD-1 and PD-L1 inhibitors (used alone or combined with chemotherapy) increased the risk of developing immune-related pneumonitis (P < 0.00001; P < 0.00001). Based on indirect analyses results (subgroup analyses), the risk of PD-L1-induced pneumonitis was weaker than that of PD-1 inhibitors when the control group was chemotherapy (OR = 3.33 vs. 5.43) or placebo (OR = 2.53 vs. 3.19), while no obvious significant differences were found (P = 0.17; P = 0.53). For the Mirror-pairing-based meta-analysis, the risk of PD-1-induced pneumonitis was significantly higher than that of PD-L1 inhibitors (OR = 1.46, 95%CI [1.08, 1.98], I2 = 0%, Z = 2.47 (P = 0.01)). However, this difference was not significant, when they were combined with chemotherapy (OR = 1.05, 95%CI [0.68, 1.60], I2 = 38%, Z = 0.21 (P = 0.84)). Conclusion: Both PD-1 and PD-L1 inhibitors increased the risk of immune-related pneumonitis, while the risk of PD-1-induced pneumonitis was significantly higher than that of PD-L1 inhibitors. [ABSTRACT FROM AUTHOR]

Tumor vaccine, a promising modality of tumor immunotherapy, needs to go through the process of tumor antigen generation and loading, antigen drainage to lymph nodes (LNs), antigen internalization by dendritic cells (DCs), DC maturation, and antigen cross-presentation to activate T-cells. However, tumor vaccines are often unable to satisfy all the steps, leading to the limitation of their application and efficacy. Herein, based on a smart nanogel system, an in situ nano-vaccine (CpG@Man-P/Tra/Gel) targeting LNs was constructed to induce potent anti-tumor immune effects and inhibit the recurrence and metastasis of ovarian cancer. The CpG@Man-P/Tra/Gel exhibited MMP-2-sensitive release of trametinib (Tra) and nano-adjuvant CPG@Man-P, which generated abundant in situ depot of whole-cell tumor antigens and formed in situ nano-vaccines with CpG@Man-P. Benefiting from mannose (Man) modification, the nano-vaccines targeted to LNs, promoted the uptake of antigens by DCs, further inducing the maturation of DCs and activation of T cells. Moreover, CpG@Man-P with different particle sizes were prepared and the effective size was selected to evaluate the antitumor effect and immune response in vivo. Notably, combined with PD-1 blocking, the vaccine effectively inhibited primary tumor growth and induced tumor-specific immune response against tumor recurrence and metastasis of ovarian cancer. A smart tumor in situ nano-vaccine Tra/CpG@Man-P/Gel was constructed, and the size of nanoadjuvants was optimixed, to induce potent antitumor immunity and inhibit the primary and metastatic tumors. [Display omitted] [ABSTRACT FROM AUTHOR]

Context Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with poor prognosis in advanced stages. While therapies targeting the checkpoint molecules programmed cell death 1 (PD-1), its ligand PD-L1, and the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have revolutionized treatment in many cancers, the results in ACCs were heterogeneous. Objective Their expression in ACC has not been systematically studied and might explain the variable response to immune checkpoint inhibitors. Methods The expression of PD-1, PD-L1 and CTLA-4 was examined in 162 tumor samples from 122 patients with ACC by immunohistochemistry (threshold of >1%) and correlated with tumoral T lymphocyte infiltration and clinical endpoints. Finally, univariate and multivariate analyses of progression-free and overall survival were performed. Results PD-1 and PD-L1 were expressed in 26.5% and 24.7% of samples, respectively, with low expression in most tumor samples (median positive cells: 2.1% and 21.7%). In contrast, CTLA-4 expression was observed in 52.5% of ACC with a median of 38.4% positive cells. Positive PD-1 expression was associated with longer progression-free survival (HR 0.50, 95% CI 0.25-0.98, P =.04) even after considering prognostic factors. In contrast, PD-L1 and CTLA-4 did not correlate with clinical outcome. Additionally, PD-1 and PD-L1 expression correlated significantly with the amount of CD3+, CD4+, FoxP3+, and CD8+ T cells. Conclusion The heterogeneous expression of PD1, PD-L1, and CTLA-4 in this large series of well-annotated ACC samples might explain the heterogeneous results of the immunotherapies in advanced ACC. In addition, PD-1 expression is a strong prognostic biomarker that can easily be applied in routine clinical care and histopathological assessment. [ABSTRACT FROM AUTHOR]

Background: Metformin, a drug prescribed for patients with type 2 diabetes, has potential efficacy in enhancing antitumor immunity; however, the detailed underlying mechanisms remain to be elucidated. Therefore, we aimed to identify the inhibitory molecular mechanisms of metformin on programmed death ligand 1 (PD-L1) expression in cancer cells and programmed death 1 (PD-1) expression in immune cells. Methods: We employed a luciferase reporter assay, quantitative real-time PCR, immunoblotting analysis, immunoprecipitation and ubiquitylation assays, and a natural killer (NK) cell-mediated tumor cell cytotoxicity assay. A mouse xenograft tumor model was used to evaluate the effect of metformin on tumor growth, followed by flow-cytometric analysis using tumor-derived single-cell suspensions. Results: Metformin decreased AKT-mediated ß-catenin S552 phosphorylation and subsequent ß-catenin transactivation in an adenosine monophosphate-activated protein kinase (AMPK) activation-dependent manner, resulting in reduced CD274 (encoding PD-L1) transcription in cancer cells. Tumor-derived soluble factors enhanced PD-1 protein stability in NK and T cells via dissociation of PD-1 from ubiquitin E3 ligases and reducing PD-1 polyubiquitylation. Metformin inhibited the tumor-derived soluble factor-reduced binding of PD-1 to E3 ligases and PD-1 polyubiquitylation, resulting in PD-1 protein downregulation in an AMPK activation-dependent manner. These inhibitory effects of metformin on both PD-L1 and PD-1 expression ameliorated cancer-reduced cytotoxic activity of immune cells in vitro and decreased tumor immune evasion and growth in vivo. Conclusions: Metformin blocks both PD-L1 and PD-1 within the tumor microenvironment. This study provided a mechanistic insight into the efficacy of metformin in improving immunotherapy in human cancer. [ABSTRACT FROM AUTHOR]

The application of CAR-T cells in solid tumors poses several challenges, including poor T cell homing ability, limited infiltration of T cells and an immunosuppressive tumor environment. In this study, we developed a novel approach to address these obstacles by designing GPC3-specific CAR-T cell that co-express IL-21 and CXCL9 (21 × 9 GPC3 CAR-T cells) and blocking the PD-1 expression on it. The proliferation, cell phenotype, cytokine secretion and cell migration of indicated CAR-T cells were evaluated in vitro. The cytotoxic activities of genetically engineered CAR-T cells were accessed in vitro and in vivo. Compared to conventional GPC3 CAR-T cells, the 21 × 9 GPC3 CAR-T cells demonstrated superior proliferation, cytokine secretion and chemotaxis capabilities in vitro. Furthermore, when combined with PD-1 blockade, the 21 × 9 GPC3 CAR-T cells exhibited enhanced proliferation, cytokine secretion and enrichment of effector T cells such as CTL, NKT and TEM cells. In xenograft tumor models, the PD-1 blocked 21 × 9 GPC3 CAR-T cells effectively suppressed HCC xenograft growth and increased T cell infiltration. Overall, our study successfully generated GPC3 CAR-T cells expressing both IL-21 and CXCL9, demonstrated that combining PD-1 blockade can further enhance CAR-T cell function by promoting proliferation, cytokine secretion, chemotaxis and antitumor activity. These findings present a hopeful and potentially effective strategy for GPC3-positive HCC patients. [ABSTRACT FROM AUTHOR]

Background: The majority of patients with lung cancer exhibit drug resistance after anti-PD-1 immunotherapy, leading to shortened patient survival time. Previous studies have suggested an association between epigenetic abnormalities such as methylation and clinical response to anti-PD-1 immunotherapy, while the role of SUMOylation in resistance to anti-PD-1 antibody immunotherapy is still unclear. Methods: Here, the mRNA expression of 15 SUMO machinery components in PBMC from lung cancer patients receiving anti-PD-1 immunotherapy were analyzed using real-time PCR. Base on the percentage change in mRNA levels, the relationship between the expression of SUMO machinery components and outcomes of anti-PD-1 immunotherapy, and the influencing factors of SUMOylation were evaluated. PBMC was treated with different concentrations of 2-D08 (a specific inhibitor of SUMOylation) in vitro, and analyzed the activation and the death rates of lymphocyte subsets by flow cytometry analysis. Results: A predictive method, base on the gene expression of three SUMO machinery components (SUMO1, SUMO3 and UBE2I), were developed to distinguish non-responders to PD-1 inhibitors. Furthermore, the number of lymphocytes in peripheral blood significantly reduced in the dysregulated SUMOylation groups (the percentage change >100 or -50 ~ -100 groups). In vitro studies confirmed that lightly low SUMOylation level improved the activation status of T and NK lymphocytes, but extremely low SUMOylation level lead to the increased death rates of lymphocytes. Conclusion: Our findings implied that dysregulated gene expression of SUMO machinery components could induce the resistance of anti-PD-1 immunotherapy in lung cancer by upregulating the death of peripheral blood lymphocytes. These data might provide effective circulating biomarkers for predicting the efficacy of anti-PD-1 immunotherapy, and uncovered a novel regulatory mechanism of resistance to anti-PD-1 immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Immune‐checkpoint inhibitors are now used more commonly in combination than monotherapy as the first‐line choice in patients with unresectable advanced melanoma. Nevertheless, for cases that progressed after the initial combination therapy, the subsequent regimen option can be very difficult. Herein, we reported the efficacy and safety of a triple combination regimen in Chinese unresectable advanced melanoma patients who had poor responses to the first‐line immune therapy. Methods: We reviewed the clinical profiles of patients diagnosed with stage IIIC‐IV melanoma between June 1, 2020, and September 30, 2023. The patients who failed the prior immune therapies and received anti‐PD‐1 mono antibody plus interferon(IFN)‐alpha 1b and anlotinib hydrochloride as the second‐line therapy were enrolled in the retrospective analysis. Additionally, we examined the exhaustion of T‐cells using mIHC staining in available tumor samples. Results: Fifty‐five patients were included in this study. The median follow‐up period was 13.6 months. The objective response rate evaluated by the investigators was 9.1%(1CR, 4PR). The disease control rate was 47.3%. The median overall survival was 17.6 months, and the median progression‐free survival was 2.8 months. The adverse events rate of any grade was 100%. Grade 3 or 4 irAEs were observed in 29.1% of cases. Multiplex immunohistochemical staining revealed an increased trend of TIM3 expression on tumor‐infiltrating T cells in patients without objective response. Conclusion: PD‐1 monoclonal antibody plus interferon‐alpha 1b plus anlotinib showed acceptable tolerability and anticancer benefits in Chinese metastatic melanoma patients as a second‐line therapy. [ABSTRACT FROM AUTHOR]

Cervical cancer (CC) poses a significant health burden, particularly in low- and middle-income countries. NK cells play a crucial role against CC; however, they can become exhausted and lose their cytotoxic capacity. This work explores the expression of costimulatory receptors (ICOS, 4-1BB, OX-40) in exhausted NK cells from CC patients. Peripheral blood and tumor biopsies were collected, and flow cytometry was used to evaluate the expression of costimulatory receptors in exhausted NK cells. There is an increase of peripheral exhausted NK cells (PD-1+TIGIT+) in CC patients; this subpopulation has a selectively increased expression of the costimulatory receptors ICOS and 4-1BB. An exhausted population is also highly increased in tumor-infiltrating NK cells, and it shows a dramatically increased expression of the costimulatory receptors ICOS (>15×) and 4-1BB (>10×) compared to peripheral NK cells. The exhausted cells, both in the periphery and in the tumor infiltrating lymphocytes (TILs), are also more likely than non-exhausted NK cell populations (PD-1−TIGIT−) to express these costimulatory receptors; increases ranging from 2.0× ICOS, 2.4× 4-1BB, and 2.6× OX-40 in CD56dim PBMCs to 1.5× ICOS, 5× 4-1BB, and 10× OX-40 in TILs were found. Our study demonstrates for the first time the increased expression of the costimulatory receptors ICOS, 4-1BB, and OX-40 in peripheral CD56dim, CD56bright, and tumor-infiltrating NK cells in CC. Targeting these receptors for stimulation could reverse exhaustion and be a promising immunotherapy strategy. [ABSTRACT FROM AUTHOR]

Dendritic cell (DC) vaccines have shown promising effects in cancer management, while low cell activity and low migration rate to lymph nodes limit their clinical application. Here, this work reports a bioink DC vaccine, synthesized by 3D printing methacryloyl gelatin to encapsulate DCs and tumor cellular vesicles overexpressing programmed cell death protein 1 (PD1‐CVs), for cancer immunotherapy. Compared with a traditional hydrogel, the porous 3D scaffold significantly improves the viability of DCs from ∼16% to ∼70% after 7 days of cell culture and increases the proportion of released DCs from the scaffold into lymph nodes by about fourfold. The PD1‐CVs stimulate DC maturation and block PD ligand‐1 (PD‐L1) in mature DCs and tumor cells, synergistically boosting DC‐mediated antitumor immunity. In breast tumor mouse models, this personalized 3D DC vaccine developed for site‐specific filling after tumor resection significantly suppress tumor recurrence and extend median survival time to 45 days. This 3D printed vaccine offers a simple, safe, and robust strategy for enhanced cell‐based cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Skeletal muscle atrophy is a known risk factor for immunosuppressive conditions and for a poor prognosis in sepsis. However, its immunopathology has not been experimentally elucidated. This study investigated the effects of skeletal muscle atrophy on the immunopathology of sepsis. Male C57BL/6J mice were subjected to sciatic denervation (DN) and caecal ligation and puncture (CLP) to induce muscle atrophy or sepsis. The macrophages, myeloid‐derived suppressor cells (MDSC), and T‐cells in peritoneal and spleen were analysed using flow cytometry. DN‐induced muscle atrophy did not affect macrophage and MDSC populations. In contrast, the percentage of cytotoxic T‐lymphocyte‐associated antigen (CTLA)‐4+ CD4+ T‐cells, programmed death (PD)‐1+ CD8+ T‐cells, regulatory T‐cells, and the CTLA‐4+ regulatory T‐cells was statistically significantly higher in DN‐CLP mice than in sham‐CLP mice. Skeletal muscle atrophy before sepsis triggers excessive T cell immunosuppression, which may contribute to the exacerbation of sepsis under skeletal muscle atrophy. [ABSTRACT FROM AUTHOR]

Background: Various inflammatory markers, including neutrophil-tolymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-tolymphocyte ratio (PLR), and C-reactive protein-to-albumin ratio (CAR), have been linked to the effectiveness of immunotherapy in multiple types of malignancies. We investigated how these inflammatory markers affect the prognosis of patients with head and neck squamous cell carcinoma (HNSCC) receiving immunotherapy. Methods: The databases PubMed, Embase, and Cochrane were systematically searched up until March 26, 2024, to identify relevant literature. Hazard ratios (HR) and corresponding 95% confidence intervals (CI) were extracted from the eligible studies. Data analysis was conducted using Review Manager and STATA 17.0 software to assess the impact of each indicator on prognosis. Subgroup analysis was performed to explore potential sources of heterogeneity in the data. Results: The analysis included sixteen studies with 1316 patients. A higher baseline NLR was significantly associated with poorer overall survival (OS) (pooled HR: 1.55, 95%CI: 1.14-2.11, P=0.006) and progression-free survival (PFS) (pooled HR: 1.59, 95% CI: 1.21-2.10, P<0.05). Furthermore, a high NLR after immunotherapy was strongly correlated with poor OS (pooled HR: 5.43, 95% CI: 3.63-8.12, P<0.01). Additionally, higher baseline C-reactive CAR was significantly associated with worse OS (pooled HR: 2.58, 95% CI: 1.96-3.40, P<0.01). Conclusion: The inflammatory markers NLR and CAR serve as effective prognostic biomarkers for immunotherapy in patients with HNSCC. However, the practical application of clinical detection requires further validation through large-scale prospective studies to confirm these findings and explore the underlying mechanisms. [ABSTRACT FROM AUTHOR]

Introduction: Inhibitors of programmed cell death 1 (PD1) and its ligand (PDL1) have exhibited favorable long-term survival in many types of advanced-stage cancer and current approvals have to date been granted in certain tumour types irrespective of PD-L1 status. Methods: We extracted the following information: study sample size, trial period, cancer types, intervention of treatment, type of PD-L1 antibody, immunohistochemistry (IHC) scoring method, number and percentage of PDL1 < 1% population, and median follow-up time. PD-L1 expression was defined as percentage of number of PD-L1-stained tumor cells (TPS), area of tumor infiltrated by PD-L1-stained immune cells (IPS), number of PD-L1-stained cells (tumor cells, lymphocytes and macrophages; CPS). Different trials used distinct method to define low PD-L1 expression. The risk of bias of the included trials was assessed by using the Cochrane risk of bias tool for RCTs. Results: Here, a total of 34 trials were included to extract individual patient data (IPD) to evaluate the survival benefit of first line PD1/PDL1 inhibitors vs. standardof-care (SOC) in patients with PDL1 < 1%. In term of anti-PD-1/PD-L1 monotherapy, OS (HR = 0.90, 0.81-1.01) and PFS (HR = 1.11, 0.97-1.27) between PD-1/PD-L1 inhibitor group and SOC group were comparable. In term of anti-PD-1/PD-L1 combination therapy, PD-1/PD-L1 inhibitor group exhibited longer OS (median 19.5 months vs. 16.3 months; HR = 0.83, 0.79-0.88, p < 0.001) and PFS than those of SOC group (median 8.11 months vs. 6.96 months; HR = 0.82, 0.77-0.87, p < 0.001). Subgroup analysis showed that survival benefit was mainly observed in non-small cell lung cancer (NSCLC) (HROS=0.74;HRPFS=0.69; p < 0.001), small-cell lung cancer (SCLC) (HROS=0.58, p < 0.001; HRPFS = 0.55, p = 0.030), esophageal squamous cell carcinoma (ESCC) (HROS = 0.62, p = 0.005; HRPFS = 0.79, p < 0.001), melanoma (HROS =0.53, p < 0.001) and nasopharyngeal carcinoma (NPC) (HRPFS = 0.35, p = 0.013). Conclusion: Anti-PD-1/PD-L1 combinational therapy rather than monotherapy exhibit survival benefit in the low PD-L1 population in the first-line setting, and the survival benefit was mainly observed in specific tumor types. [ABSTRACT FROM AUTHOR]

Background Acute interstitial nephritis (AIN) related to immune checkpoint inhibitors (ICI-AIN) has a not completely understood pathophysiology. Our objectives were to analyze possible biomarkers for the differentiation between acute tubular necrosis (ATN) and AIN, especially in cancer patients, and to study the participation of the immune checkpoint pathway in ICI-AIN. Methods We performed an observational study. We recruited patients with incident diagnosis of ICI-AIN (n  = 19). We measured soluble PD-1 (sPD-1), sPD-L1, and sPD-L2 in serum and urine at diagnosis and compared to it patients with non-ICI-related AIN (non-ICI-AIN) (n  = 18) and ATN (n  = 21). The findings were validated in an independent cohort from another institution (n  = 30). Also, we performed PD-L1 and PD-L2 immunostaining of kidney biopsies from patients with ICI-AIN and compared to patients with non-ICI-AIN. Results Urinary sPD-1 (usPD-1) was higher in patients with AIN compared to ATN (P  = .03). Patients with AIN also showed higher serum sPD-1 (ssPD-1) than patients with ATN (P  = .021).  In cancer patients, usPD-1 <129.3 pg/ml had a 71.43% sensitivity and 94.44% specificity to differentiate ATN from ICI-AIN, with a likelihood ratio of 12.86. In the external validation cohort, the same cutoff showed a sensitivity of 80%.  In kidney biopsies, patients with ICI-AIN showed higher density of PD-L1 positive tubules than patients with non-ICI-AIN (P  = .02). The proportion of patients having >2.64/mm2 PD-L2 positive tubules was higher among patients with ICI-AIN compared to non-ICI-AIN (P  = .034). There was a positive correlation (P  = .009, r  = 0.72) between usPD-1 and the number of PD-L1 positive tubules. Conclusions UsPD-1 and ssPD-1 are higher in AIN than ATN. Moreover, there was a strong correlation between usPD-1 and renal tubular PD-L1 expression. Our findings suggest a role of usPD-1 as non-invasive biomarker to differentiate ICI-AIN from ATN, especially in cancer patients, which has been confirmed in an external validation cohort. [ABSTRACT FROM AUTHOR]

Idiosyncratic drug reactions (IDRs) are associated with significant patient morbidity/mortality and lead to considerable drug candidate attrition in drug development. Their idiosyncratic nature makes the study of IDRs difficult. In particular, nevirapine is associated with a relatively high risk of serious skin rash and liver injury. We previously found that nevirapine causes a similar skin rash in female Brown Norway rats, but these animals do not develop significant liver injury. Programmed cell death protein-1 (PD-1) is an immune checkpoint involved in immune tolerance, and anti-PD-1 antibodies have been used to treat cancer. However, they increase the risk of liver injury caused by co-administered drugs. We found that PD-1−/− mice are more susceptible to drug-induced liver injury, but PD-1−/− mice are not a good model for all drugs. In particular, they do not develop a skin rash when treated with nevirapine, at least in part because they lack the sulfotransferase in their skin that forms the reactive metabolite responsible for the rash. Therefore, we developed a PD-1 mutant (PD-1m/m) rat, with an excision in the ligand-binding domain of PD-1, to test whether nevirapine would cause a more serious skin rash in these animals. The PD-1m/m rat was based on a Sprague Dawley background, which has a lower incidence of skin rash than Brown Norway rats. The treated PD-1m/m rats developed more severe liver injury than PD-1−/− mice, but in contrast to expectations, they did not develop a skin rash. Functional knockouts provide a unique tool to study the mechanisms of IDRs. [ABSTRACT FROM AUTHOR]

Background: Anti-programmed cell death-1 (ligand-1) antibody [PD-(L)1-Ab] can cause destructive thyroiditis and/or hypothyroidism. In addition, tyrosine kinase inhibitors (TKIs) frequently induce hypothyroidism. The aim of this prospective study is to examine the incidence and clinical characteristics of thyroid dysfunction induced by combination therapy of a PD-(L)1-Ab and TKI [PD-(L)1-Ab/TKI]. Methods: A total of 757 patients treated with PD-(L)1-Ab or PD-(L)1-Ab/TKI were evaluated for anti-thyroid antibodies (ATAs) at baseline and for thyroid function for 48 weeks after treatment initiation and then observed until the last visit. Results: The cumulative incidences of destructive thyroiditis [4/23 (17.4%) vs. 45/734 (6.1%) patients, p < 0.001], isolated hypothyroidism [10/23 (43.5%) vs. 29/734 (4.0%) patients, p < 0.001], and all thyroid dysfunction [14/23 (60.9%) vs. 74/734 (10.1%) patients, p < 0.001] were significantly higher in the PD-(L)1-Ab/TKI group than PD-(L)1-Ab group, respectively. All patients positive for ATAs at baseline developed thyroid dysfunction after PD-(L)1-Ab/TKI treatment, a significantly higher incidence than that in those negative for ATAs at baseline [4/4 (100%) vs. 10/19 (52.6%) patients, p = 0.026]. Conclusions: The addition of TKIs increased the risk of thyroid dysfunction induced by PD-(L)1-Ab, with the risk being higher in patients positive for baseline ATAs. [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate the relationship between signal regulatory protein gamma (SIRPG) and tumor immune microenvironment phenotypes or T cell mediated-adaptive antitumor immunity, and its predictive value for response to PD-1 blockade in cancers. Methods: Pan-cancer analysis of SIRPG expression and immune deconvolution was performed using transcriptomic data across 33 tumor types. Transcriptomic and clinical data from 157 patients with non-small-cell lung cancer (NSCLC) and melanoma received PD-1 blockade were analyzed. Expression characteristics of SIRPG were investigated using single-cell RNA sequencing (scRNA-seq) data of 103,599 cells. The effect of SIRPG expression was evaluated via SIRPG knockdown or overexpression in Jurkat T cells. Results: The results showed that most cancers with high SIRPG expression had significantly higher abundance of T cells, B cells, NK cells, M1 macrophages and cytotoxic lymphocytes and increased expression level of immunomodulatory factors regulating immune cell recruitment, antigen presentation, T cell activation and cytotoxicity, but markedly lower abundance of neutrophils, M2 macrophages, and myeloid-derived suppressor cells. High SIRPG expression was associated with favorable response to PD-1 blockade in both NSCLC and melanoma. scRNA-seq data suggested SIRPG was mainly expressed in CD8+ exhausted T and CD4+ regulatory T cells, and positively associated with immune checkpoint expression including PDCD1 and CTLA4. In vitro test showed SIRPG expression in T cells could facilitate expression of PDCD1 and CTLA4. Conclusion: High SIRPG expression is associated with an inflamed immune phenotype in cancers and favorable response to PD-1 blockade, suggesting it would be a promising predictive biomarker for PD-1 blockade and novel immunotherapeutic target. [ABSTRACT FROM AUTHOR]

Single-chain Fv (scFv) is a recombinant small antibody in which a polypeptide linker connects the variable regions of the light chain (VL) and the heavy chain (VH). The practical use of scFv, however, has been prevented by its tendency to aggregate due to interchain VL–VH interactions. We recently developed a cyclic scFv whose N-terminus and C-terminus were connected by protein ligation techniques. Biophysical comparisons between cyclic and linear scFv have been conducted, but cell biological evaluations remain unexplored. Here we studied the properties of cyclic and linear scFv derived from nivolumab. Biophysical studies revealed that the thermal stability was not changed but that the antigen-binding activity was approximately 3-fold higher as a result of circularization. A cell-based PD-1/PD-L1 interaction inhibitory assay revealed that the biological activity of scFv was markedly higher in the circularized form. In addition, biophysical analysis of scFv proteins incubated in the presence of serum revealed that circularization suppressed the decrease in antigen-binding activity. It could be assumed that circularization of scFv improved stability in the presence of serum, which in turn would suggest the applicability of cyclic scFv as a biopharmaceutical format. [ABSTRACT FROM AUTHOR]

CX3CL1 is one of the 50 up-to-date identified and characterized chemokines. While other chemokines are produced as small, secreted proteins, CX3CL1 (fractalkine) is synthetized as a transmembrane protein which also leads to a soluble form produced as a result of proteolytic cleavage. The membrane-bound protein and the soluble forms exhibit different biological functions. While the role of the fractalkine/CX3CR1 signaling axis was described in the nervous system and was also related to the migration of leukocytes to sites of inflammation, its actions are controversial in cancer progression and anti-tumor immunity. In the present review, we first describe the known biology of fractalkine concerning its action through its cognate receptor, but also its role in the activation of different integrins. The second part of this review is dedicated to its role in cancer where we discuss its role in anti-cancer or procarcinogenic activities. [ABSTRACT FROM AUTHOR]

With the advancement of cancer treatment technologies, immunotherapy has begun to be widely utilized. Colon cancer is one of the most common types of cancer, with metastasis being a frequent occurrence in late-stage patients. Hence, immunotherapy, as an emerging and potentially effective treatment modality, merits exploration to enhance patient survival rates and clinical benefits. However, various immune-related adverse events cannot be entirely avoided. Myasthenia gravis induced by immunotherapy serves as a rare but potentially lethal adverse event, and it has been increasingly reported. Understanding the mechanisms of irAEs can aid in controlling the side effects induced by treatment. Here, we reported a case of myasthenia gravis occurring after anti-PD-1 therapy for late-stage colon cancer. [ABSTRACT FROM AUTHOR]

In this study, the immunohistochemical expression of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1), which could facilitate a novel approach to immunotherapy for feline injection site sarcomas (FISSs), was investigated. Treatment strategies based on the suppression of this pathway are possible for tumours expressing PD-1/PD-L1. In this context, FISSs were histologically classified, the grade of sarcoma and the intensity of lymphocyte infiltration determined and PD-1 and PD-L1 expression evaluated in tumours of different grade. Tumours were immunolabelled for vimentin, S100, smooth muscle actin and sarcomeric actin. Fibrosarcoma was diagnosed in eight cases, undifferentiated sarcoma in one case, liposarcoma in one case and rhabdomyosarcoma in one case. PD-1 expression was found mainly in lymphoid infiltrations and macrophage-like cells, while PD-L1 was found primarily in tumour cells and infiltrated macrophage-like cells. By Pearson correlation analysis, tumour differentiation was found to have a moderate correlation with PD-1 (P <0.05) and a high correlation with PD-L1 (P <0.01). Tumour grade had a low correlation with PD-1 and a moderate correlation with PD-L1 (P >0.05). A moderate correlation was also detected between PD-1 and PD-L1 (P <0.05). It was concluded that the increased expression of PD-1 and PD-L1 may be associated with poor tumour differentiation and, therefore, poor prognosis in FISS. [ABSTRACT FROM AUTHOR]

Glucagon‐like peptide‐1 (GLP‐1) regulates glycemic excursions by augmenting insulin production and inhibiting glucagon secretion. Liraglutide, a long‐acting GLP‐1 analog, can improve glycemic control for treating type 2 diabetes and prevent neutrophil extravasation in inflammation. Here, we explored the role of liraglutide in the development and therapy of murine lung and liver cancers. In this study, liraglutide substantially decreased circulating neutrophil extracellular trap (NET) markers myeloperoxidase, elastase, and dsDNA in Lewis lung cancer (LLC) and Hepa1‐6 tumor‐bearing mice. Furthermore, liraglutide downregulated NETs and reactive oxygen species (ROS) of neutrophils in the tumor microenvironment. Functionally, in vitro experiments showed that liraglutide reduced NET formation by inhibiting ROS. In addition, we showed that liraglutide enhanced the anti‐tumoral efficiency of programmed cell death‐1 (PD‐1) inhibition in LLC and Hepa1‐6 tumor‐bearing C57BL/6 mice. However, the removal of NETs significantly weakened the antitumor efficiency of liraglutide. We further demonstrated that the long‐term antitumor CD8+ T cell responses induced by the combination therapy rejected rechallenges by respective tumor cell lines. Taken together, our findings suggest that liraglutide may promote the anti‐tumoral efficiency of PD‐1 inhibition by reducing NETs in lung and liver cancers. [ABSTRACT FROM AUTHOR]

Purpose: The majority of new diagnoses of hepatocellular carcinoma (HCC) still pertain to unresectable cases. Currently, the combination therapy of tyrosine kinase inhibitors (TKIs) and programmed cell death protein-1 (PD-1) inhibitors has become the mainstream treatment. According to multiple clinical guidelines, it is strongly advised to consider local therapy as the primary treatment choice for uHCC. This research was conducted to examine the safety and effectiveness of combining hepatic arterial infusion chemotherapy (HAIC) with TKIs and PD-1 inhibitors for the treatment of uHCC. Methods: Between 2015 and 2020, 208 HCC patients received HAIC alone or HAIC in combination with TKIs and PD-1 inhibitors. The overall survival(OS), and progression-free survival(PFS) and the best treatment response were compared between the two treatment groups. Propensity score matching (PSM)was used to minimize confounding bias. Results: Among the enrolled patients, 116 patients (55.8%) received combination therapy, while 92 patients (44.2%) received HAIC alone. The baseline characteristics were similar between the two groups. After PSM, 82 pairs of well-matched liver cancer patients were selected; the overall response rate in the combination group trended better than that in the HAIC alone group. The hazard ratios (HRs) for OS and PFS of the combination approach compared to the HAIC-alone approach were 0.47 (95% CI, 0.322– 0.687; p< 0.001) and 0.58 (95% CI, 0.397– 0.848; p=0.005), respectively. Conclusion: For uHCC patients, combination therapy can provide better OS and PFS compared to HAIC alone. [ABSTRACT FROM AUTHOR]

Purpose of Review: Given the rapid development of multiple targeted and immune therapies for patients with advanced melanoma, it can be challenging to select a therapy based on currently available data. This review aims to provide an overview of frontline options for metastatic melanoma, with practical guidance for selecting a treatment regimen. Recent Findings: Recently reported data from randomized trials suggests that the majority of patients with unresectable melanoma should receive a PD-1 checkpoint inhibitor as part of their first line therapy, irrespective of BRAF mutation status. Additional data also suggests that combination immunotherapies result in improved outcomes compared to single agent, albeit at the cost of increased toxicity, though to date no biomarker exists to help guide treatment selection. Summary: As the number therapeutic options continue to grow for patients with advanced melanoma, there is likely to be a continued focus on combination strategies. Defining the optimal treatment approach in order to maximize efficacy while minimizing toxicity remains an area of active investigation. [ABSTRACT FROM AUTHOR]

Programmed cell death-1 (PD-1) is an immunoinhibitory receptor required to suppress inappropriate immune responses such as autoimmunity. Immune checkpoint antibodies that augment the PD-1 pathway lead to immune-related adverse events (irAEs), organ non-specific side effects due to autoimmune activation in humans. In this study, we generated a PD-1 mutant pig using electroporation-mediated introduction of the CRISPR/Cas9 system into porcine zygotes to evaluate the PD-1 gene deficiency phenotype. We optimized the efficient guide RNAs (gRNAs) targeting PD-1 in zygotes and transferred electroporated embryos with the optimized gRNAs and Cas9 into recipient gilts. One recipient gilt became pregnant and gave birth to two piglets. Sequencing analysis revealed that both piglets were biallelic mutants. At 18 mo of age, one pig showed non-purulent arthritis of the left elbow/knee joint and oligozoospermia, presumably related to PD-1 modification. Although this study has a limitation because of the small number of cases, our phenotypic analysis of PD-1 modification in pigs will provide significant insight into human medicine and PD-1-deficient pigs can be beneficial models for studying human irAEs. [ABSTRACT FROM AUTHOR]

Immune checkpoints are mechanisms that allow cancer cells to evade immune surveillance and avoid destruction by the body's immune system. Tumor cells exploit immune checkpoint proteins to inhibit T cell activation, thus enhancing their resistance to immune attacks. Immune checkpoint inhibitors, like nivolumab, work by reactivating these suppressed T cells to target cancer cells. However, this reactivation can disrupt immune balance and cause immune-related adverse events. This report presents a rare case of prurigo nodularis that developed six months after administering nivolumab for lung adenocarcinoma. While immune-related adverse events are commonly linked to T helper-1- or T helper-17-type inflammations, T helper-2-type inflammatory reactions, as observed in our case, are unusual. The PD-1–PD-L1 pathway is typically associated with T helper-1 and 17 responses, whereas the PD-1–PD-L2 pathway is linked to T helper-2 responses. Inhibition of PD-1 can enhance PD-L1 functions, potentially shifting the immune response towards T helper-1 and 17 types, but it may also influence T helper-2-type inflammation. This study reviews T helper-2-type inflammatory diseases emerging from immune checkpoint inhibitor treatment, highlighting the novelty of our findings. [ABSTRACT FROM AUTHOR]

Many cancer patients do not benefit from PD-L1/PD-1 blockade immunotherapies. PD-1 and LAG-3 co-upregulation in T-cells is one of the major mechanisms of resistance by establishing a highly dysfunctional state in T-cells. To identify shared features associated to PD-1/LAG-3 dysfunctionality in human cancers and T-cells, multiomic expression profiles were obtained for all TCGA cancers immune infiltrates. A PD-1/LAG-3 dysfunctional signature was found which regulated immune, metabolic, genetic, and epigenetic pathways, but especially a reinforced negative regulation of the TCR signalosome. These results were validated in T-cell lines with constitutively active PD-1, LAG-3 pathways and their combination. A differential analysis of the proteome of PD-1/LAG-3 T-cells showed a specific enrichment in ubiquitin ligases participating in E3 ubiquitination pathways. PD-1/LAG-3 co-blockade inhibited CBL-B expression, while the use of a bispecific drug in clinical development also repressed C-CBL expression, which reverted T-cell dysfunctionality in lung cancer patients resistant to PD-L1/PD-1 blockade. The combination of CBL-B-specific small molecule inhibitors with anti-PD-1/anti-LAG-3 immunotherapies demonstrated notable therapeutic efficacy in models of lung cancer refractory to immunotherapies, overcoming PD-1/LAG-3 mediated resistance. Synopsis: PD-1/LAG-3 molecular mechanism of co-signaling was identified in T-cells, and combination of CBL-B inhibitors with anti-PD-1/anti-LAG-3 immunotherapies overcame PD-1/LAG-3-mediated resistance in models of lung cancer refractory to immunotherapies. PD-1/LAG-3 co-signaling regulates a highly dysfunctional signature in T-cells. CBL E3 ubiquitin ligases are key targets associated to the regulation of PD-1/LAG-3 mediated T-cell dysfunctional pathways in cell lines and primary cells from NSCLC patients. PD-1, LAG-3 and CBL-B triple blockade overcomes PD-1/LAG-3 mediated resistance and T-cell dysfunctionality in a lung cancer model refractory to immunotherapies. CD8 T cells are responsible for the PD-1, LAG-3 and CBL-B triple blockade therapeutic antitumor effect. Patients with dysfunctional T-cell immunity resistant to conventional antibody blockade immunotherapies could benefit from immunotherapy blockade combined with CBL-B inhibitors. PD-1/LAG-3 molecular mechanism of co-signaling was identified in T-cells, and combination of CBL-B inhibitors with anti-PD-1/anti-LAG-3 immunotherapies overcame PD-1/LAG-3-mediated resistance in models of lung cancer refractory to immunotherapies. [ABSTRACT FROM AUTHOR]

During tumorigenesis and progression, the immune checkpoint programmed death-1 (PD-1) and its ligand programmed death ligand-1 (PD-L1) play critical roles in suppressing T cell-mediated anticancer immune responses, leading to T-cell exhaustion and subsequent tumor evasion. Therefore, anti-PD-L1/PD-1 therapy has been an attractive strategy for treating cancer over the past decade. However, the overall efficacy of this approach remains suboptimal, revealing an urgent need for novel insights. Interestingly, increasing evidence indicates that both PD-L1 on tumor cells and PD-1 on tumor-specific T cells undergo extensive N-linked glycosylation, which is essential for the stability and interaction of these proteins, and this modification promotes tumor evasion. In various preclinical models, targeting the N-linked glycosylation of PD-L1/PD-1 was shown to significantly increase the efficacy of PD-L1/PD-1 blockade therapy. Furthermore, deglycosylation of PD-L1 strengthens the signal intensity in PD-L1 immunohistochemistry (IHC) assays, improving the diagnostic and therapeutic relevance of this protein. In this review, we provide an overview of the regulatory mechanisms underlying the N-linked glycosylation of PD-L1/PD-1 as well as the crucial role of N-linked glycosylation in PD-L1/PD-1-mediated immune evasion. In addition, we highlight the promising implications of targeting the N-linked glycosylation of PD-L1/PD-1 in the clinical diagnosis and treatment of cancer. Our review identifies knowledge gaps and sheds new light on the cancer research field. [ABSTRACT FROM AUTHOR]

Background: Advanced head and neck squamous cell carcinoma (HNSCC) has a poor prognosis, and new treatment options are needed. Combining immunotherapies with differing mechanisms of action may enhance clinical benefits compared with single-agent immunotherapy. Epacadostat, an indoleamine 2,3 dioxygenase 1 inhibitor, plus pembrolizumab, a PD-1 inhibitor, showed promising activity in advanced HNSCC in the phase 1/2 KEYNOTE-037/ECHO-202 trial. Methods: KEYNOTE-669/ECHO-304 is a randomized, open-label, phase 3 study evaluating the efficacy and safety of pembrolizumab plus epacadostat, pembrolizumab monotherapy, and the EXTREME regimen (cetuximab with a platinum [carboplatin or cisplatin] and 5-fluorouracil) in recurrent/metastatic (R/M) HNSCC. Participants had no prior systemic therapy for R/M HNSCC and were randomly assigned (2:1:2) to pembrolizumab 200 mg intravenously every 3 weeks plus epacadostat 100 mg orally twice daily, pembrolizumab monotherapy, or EXTREME. The primary endpoint was objective response rate (ORR; investigator assessment). Secondary endpoints were safety and tolerability. Change in serum kynurenine was an exploratory endpoint. Study enrollment was discontinued early as a strategic decision on May 2, 2018, and response assessment was discontinued after first on-study imaging assessment at week 9. Data cut-off was January 17, 2019. Results: Between December 1, 2017, and May 2, 2018, 89 patients were randomly allocated to pembrolizumab plus epacadostat (n = 35), pembrolizumab monotherapy (n = 19), or EXTREME (n = 35). ORR (95% CI) was 31% (17%–49%) for pembrolizumab plus epacadostat, 21% (6%–46%) for pembrolizumab monotherapy, and 34% (19%–52%) for EXTREME. Treatment-related adverse events (TRAEs) occurred in 82% (n = 28) of patients receiving pembrolizumab plus epacadostat, 63% (n = 12) receiving pembrolizumab monotherapy, and 100% (n = 34) receiving EXTREME. Grade 3–4 TRAEs occurred in 24% (n = 8) of patients receiving pembrolizumab plus epacadostat, 16% (n = 3) receiving pembrolizumab monotherapy, and 82% (n = 28) receiving EXTREME. No deaths occurred due to AEs. Pembrolizumab plus epacadostat treatment reduced kynurenine levels but not to that of healthy subjects. Conclusions: Pembrolizumab plus epacadostat and pembrolizumab monotherapy provided a similar response rate to EXTREME and demonstrated a manageable safety profile in patients with R/M HNSCC. Trial registration: NCT03358472. Date of trial registration: November 30, 2017. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusions Programmed cell death receptor (ligand)‐1 inhibitors (PD‐(L)1), as the preferred immunotherapy, have been widely used in the Chinese mainland and drug‐induced liver injury (DILI) has been reported. The study aimed to investigate the clinical features or risk factors for immunotherapy‐related DILI.Patients who received PD‐(L)1 inhibitors from January 2020 to July 2021 were retrospectively reviewed. The likelihood of DILI was adjudicated by the Roussel‐Uclaf causality assessment.A total of 1175 patients were included in the study and 89 patients (7.6%) developed DILI, of which 12 (13.5%) progressed to acute liver failure (ALF) and three (3.4%) died. Among the DILI population, 56 (62.9%) had a cholestatic pattern and exhibited a prolonged treatment course and duration for resolution compared to the hepatocellular and mixed patterns. Hepatocellular carcinoma (HCC), hepatitis B virus (HBV) and abnormal baseline of alkaline phosphatase (ALP) had increased risks of DILI by 2.1‐fold (95% confidence interval [CI], 1.231–3.621), 1.9‐fold [95% CI, 1.123–3.325] and 2.1‐fold [95% CI, 1.317–3.508], respectively. The model for end‐stage liver disease (MELD) score had a c‐statistic of 0.894 (95% CI, 0.778–1.000) with a sensitivity of 67% and a specificity of 95% for poor outcomes. COX analysis showed that the MELD ≥ 18 was predictive of immunotherapy‐related ALF or death.PD‐(L)1 inhibitor‐related liver injury manifests primarily as a cholestatic pattern, on which corticosteroid treatment has minimal effect compared to hepatocellular and mixed patterns. MELD score ≥ 18 at the time of liver injury performed best in the prediction of ALF or death in immune checkpoint inhibitor (ICI)‐related DILI. [ABSTRACT FROM AUTHOR]

Despite advances in understanding systemic lupus erythematosus (SLE), many challenges remain in unraveling the precise mechanisms behind the disease's development and progression. Recent evidence has questioned the role of programmed cell death protein 1 (PD-1) in suppressing autoreactive CD4+ T cells during autoimmune responses. Research has investigated the potential impacts of PD-1 on various CD4+ T-cell subpopulations, including T follicular helper (Tfh) cells, circulating Tfh (cTfh) cells, and T peripheral helper (Tph) cells, all of which exhibit substantial PD-1 expression and are closely related to several autoimmune disorders, including SLE. This review highlights the complex role of PD-1 in autoimmunity and emphasizes the imperative for further research to elucidate its functions during autoreactive T-cell responses. Additionally, we address the potential of PD-1 and its ligands as possible therapeutic targets in SLE. [ABSTRACT FROM AUTHOR]

Objective: To observe the effect of xindili monoclonal antibody injection combined with oxaliplatin and capecitabine (XELOX) regimen on the expression of programmed death receptor-1 (PD-1) and programmed death ligand-1 (PD-L1) and peripheral blood myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Treg) in patients with advanced gastric cancer. Methods: 121 patients with advanced gastric cancer received in our hospital from April 2021 to March 2023 were selected. Patients were divided into control group (n=60, received XELOX regimen) and observation group (n=61, received xindili monoclonal antibody injection combined with XELOX regimen) according to the random number table method. The efficacy, incidence of adverse reactions, tumor markers, relative expression of PD-1 and PD-L1 mRNA, and the ratio of Treg and MDSCs to peripheral blood mononuclear cells (PBMC) were compared between two groups. Results: Compared with the ORR(25.00 %) and DCR (48.33 %) in control group, the ORR (40.98 %) and DCR (73.77 %) in observation group were higher (P<0.05). After treatment, the relative expression of carbohydrate antigen 125 (CA125), carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC-Ag), PD-1, PD-L1 mRNA, the ratio of Treg and MDSCs to PBMC in observation group were lower than those in control group(P<0.05). There was no difference in the incidence of adverse reactions between two groups (P>0.05). Conclusion: Xindili monoclonal antibody injection combined with XELOX regimen in the treatment of patients with advanced gastric cancer, which can reduce the level of serum tumor markers, regulate the expression of PD-1, PD-L1 and the ratio of Treg and MDSCs to PBMC, and effectively control the progression of the disease. [ABSTRACT FROM AUTHOR]

Objective: To analyze the efficacy and adverse effects of anti‐PD‐1 immune checkpoint inhibitors aimed at nasopharyngeal carcinoma (NPC). Methods: During the first stage of the study, using 40 patients with stage III/IVa NPC treated with anti‐PD‐1 immune checkpoint inhibitors in combination with chemoradiotherapy as a first‐line treatment (observation group) and 70 patients with NPC treated with chemoradiotherapy alone (control group). In the second stage of the study, 88 patients with NPC treated with immune checkpoint inhibitors were grouped according to the number of lines of immunotherapy, the number of times, and the types of application. Results: Observation of the short‐term effects in the first stage indicated that the objective response rate (ORR) of the observation group and the control group against primary foci of NPC was 75.0% versus 40.0%; the mortality rate of the observation group was much lower than that of the control group. The overall first‐line treatment evaluation of the observation vs. control groups were as follows: ORR (67.5% vs. 38.6%); median PFS (17.52 vs. 17.21 months); and median OS (18.68 vs. 18.14 months), respectively (p < 0.05). The second stage of the study had an ORR of 53.4%, and the efficacy of immunotherapy was related to staging, timing, and frequency. Conclusion: Anti‐PD‐1 immune checkpoint inhibitors combined with chemoradiotherapy as the first‐line treatment for nasopharyngeal carcinoma may improve patient outcomes significantly. Timing, frequency, and the type of immunotherapy exerted an effect on the efficacy of immunotherapy. Adverse effects that occurred during treatment were tolerable and controllable. [ABSTRACT FROM AUTHOR]

AMG 256 is a bi-specific, heteroimmunoglobulin molecule with an anti-PD-1 antibody domain and a single IL-21 mutein domain on the C-terminus. Nonclinical studies in cynomolgus monkeys revealed that AMG 256 administration led to the development of immunogenicity-mediated responses and indicated that the IL-21 mutein domain of AMG 256 could enhance the antidrug antibody response directed toward the monoclonal antibody domain. Anti- AMG 256 IgE were also observed in cynomolgus monkeys. A first-in-human (FIH) study in patients with advanced solid tumors was designed with these risks in mind. AMG 256 elicited ADA in 28 of 33 subjects (84.8%). However, ADA responses were only robust and exposure-impacting at the 2 lowest doses. At mid to high doses, ADA responses remained low magnitude and all subjects maintained exposure, despite most subjects developing ADA. Limited drugspecific IgE were also observed during the FIH study. ADA responses were not associated with any type of adverse event. The AMG 256 program represents a unique case where nonclinical studies informed on the risk of immunogenicity in humans, due to the IL-21-driven nature of the response. [ABSTRACT FROM AUTHOR]

Background/aim: Meningiomas are the most common primary brain tumors of the central nervous system. Immunotherapy is a promising treatment method applied in many types of cancer. There is no standard and effective medical treatment to reduce recurrence and mortality in cases of incomplete resection of meningiomas and in high-grade cases. In order to investigate medical treatments in addition to surgery and radiotherapy, in this study, the status of immune checkpoint molecules (PD-L1/PD-1), which are the target of immunotherapy, in meningiomas was investigated. Materials and methods: Four hundred two cases of meningioma diagnosed between 2007 and 2020 at our institution were used. New blocks were prepared from the appropriate blocks of the cases using the tissue microarray method. Sections obtained from these blocks were immunohistochemically stained with PD-1 and PD-L1 antibodies. Obtained data were interpreted with statistical analysis. Results: Expression of PD-L1 was observed in 28.4% of meningiomas. Staining rates are higher in high-grade tumors. The staining rate of PD-L1 in the tumor increased significantly with pattern loss. PD-L1 expression in immune cells is 19.9%. Immune cell expression and the number of expressing immune cells correlate with spontaneous necrosis. Immune cell expression and the number of expressing immune cells are increased in high-grade meningiomas. PD-1 expression in immune cells is 9.0%, and this correlates with brain invasion. Conclusions: With these data, it was observed that the expression of immune checkpoint molecules PD-L1 and PD-1 increased especially in high-grade meningiomas. It may be the subject of research that these molecules may be targets of immunotherapy in the treatment of meningiomas. [ABSTRACT FROM AUTHOR]

In this paper, a mathematical ordinary differential tumor-immune model is proposed based on an immune checkpoint inhibitor, which is an innovative method for tumor immunotherapies. Two important factors in tumor-immune response are the programmed cell death protein 1 (PD-1) and its ligand PD-L1. The model consists of three populations: tumor cells, activated T cells and anti-PD-1. By analyzing the dynamics of the model, it is found that there is always a unique tumor-free equilibrium and at most two tumor interior equilibria. The nonexistence of nontrivial positive periodic orbits is established by using the new Dulac function, and then a global dynamics of the model is obtained. The conclusions of our analysis show that increasing the possibility of T cells killing tumor cells (p), early detection of tumor cells, or the use of PD-1 inhibitors to activate T cells are effective in eliminating tumor cells. [ABSTRACT FROM AUTHOR]

Early reports of PD-1 inhibition in ovarian clear cell carcinomas (OCCC) demonstrate promising response. We evaluated the combination of pembrolizumab and IDO-1 inhibitor epacadostat in patients with recurrent OCCC. This single arm, two-stage, phase 2 trial included those with measurable disease and 1–3 prior regimens. Patients received intravenous pembrolizumab 200 mg every 3 weeks and oral epacadostat 100 mg twice a day. Primary endpoint was overall response rate (ORR), secondary endpoints were toxicity, progression-free survival (PFS) and overall survival (OS). The study was powered to detect an absolute 25% increase in response (15% to 40%). Between September 28, 2018 and April 10, 2019, 14 patients enrolled at first stage. Rate of accrual was 2.3 patients per month. Median age was 65 years (44–89), 10 (71.4%) had ≥2 prior regimens. ORR was 21% (95% CI 5–51%) within 7 months of study entry with 3 partial responses, and 4 had stable disease (disease control rate 50%). Median PFS was 4.8 months (95% CI: 1.9–9.6), OS 18.9 months (95% CI: 1.9-NR). Most common grade ≥ 3 adverse events were electrolyte abnormalities and gastrointestinal pain, nausea, vomiting, bowel obstruction. In July 2019, the study reached the pre-specified criteria to re-open to second stage; however, the study closed prematurely in February 2021 due to insufficient drug supply. Pembrolizumab and epacadostat demonstrated an ORR of 21% in this small cohort of recurrent OCCC. The rapid rate of accrual highlights the enthusiasm and need for therapeutic studies in patients with OCCC. • Pembrolizumab and epacadostat had an overall response rate of 21% in this cohort of recurrent ovarian clear cell carcinomas. • It is difficult to conclude whether this is an effective combination given the underpowered sample size due to early closure. • Rapid accrual in the first stage surpassed the estimated accrual rate, highlighting the need for trials for this rare tumor. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigates the prognostic value of C-reactive protein (CRP) kinetics in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M-HNSCC) treated with checkpoint inhibitors (CPI). We analyzed data from 44 patients treated between 2018 and 2023, applying two existing CRP classifications and developing a new one. While the existing classifications did not correlate with overall survival (OS), our novel CRP kinetic classification showed a significant association with OS (p = 0.05). Multivariate analysis identified our CRP classification (p = 0.007) and the outcome of the first re-staging (p = 0.002) as independent prognostic factors. These findings suggest that our new CRP kinetic classification could serve as a valuable prognostic marker for R/M-HNSCC patients undergoing CPI therapy, though further validation with larger patient cohorts is needed. Introduction The kinetic of C-reactive protein (CRP) in the early phase of therapy with checkpoint inhibitors (CPI) and its prognostic value has already been investigated in several tumor entities. In particular, flare dynamics have been described as a positive prognostic parameter. The aim of this retrospective study is to examine the extent to which such an application can also be transferred to patients with recurrent or metastatic squamous cell carcinoma of the head and neck region (R/M-HNSCC). Material and Methods All patients treated with CPI for R/M-HNSCC at our clinic between 2018 and 2023 were included (n = 44). Demographic, clinical, histopathologic and laboratory data were extracted from the digital patient records and statistically analyzed. We then examined the CRP kinetic using two previously published classifications and proposed a new classification ourselves. Subsequently, correlation analyses were performed with the overall survival (OS) of the patients. Results Of the two CRP kinetic classifications previously published, only one showed a correlation with the result of the first re-staging, and neither showed a correlation with the OS of R/M-HNSCC patients. Our new CRP kinetic classification showed a significant association with OS in R/M-HNSCC patients (p = 0.05). In a multivariate analysis, our CRP kinetic classification (p = 0.007) and the outcome of the first re-staging (p = 0.002) were significant independent factors for OS. Discussion Our novel CRP kinetic classification significantly correlates with OS in R/M-HNSCC patients, indicating a potential prognostic marker. Existing classifications from other cancer entities showed limited prognostic significance, emphasizing the need for tailored markers. For validation, however, testing on larger R/M-HNSCC patient collectives is necessary. [ABSTRACT FROM AUTHOR]