Programmed Death-ligand 1 Blockade Therapy Research Articles

Association analysis of FXYD5 with prognosis and immunological characteristics across pan-cancer

BackgroundThe FXYD domain-containing ion transport regulator 5 (FXYD5) gene is a cancer promoter. However, evidence for an association between FXYD5 and various types of cancer is still lacking. Using multi-omics bioinformatics, our study aimed to reveal the expression distribution, prognostic value, immune infiltration correlation, and molecular functions of FXYD5. MethodsUsing pan-cancer multi-omics data (including The Cancer Genome Atlas, PrognoScan, Gene Expression Profiling Interactive Analysis, cBioPortal, Gene Expression Omnibus, TIMER and scTIME Portal), we assessed the differences in the expression and prognostic value of FXYD5 in malignant tumors. Furthermore, at the single-cell level, we analyze the expression distribution of FXYD5 across different cell types within the tumor microenvironment, and its relationship with the immune microenvironment. Finally, focusing on ovarian cancer, we conducted preliminary validation of the above findings using cell and molecular biology techniques. ResultsOur results indicated that FXYD5 was up-regulated in various tumor types and was positively associated with tumor progression. We also revealed that FXYD5 was ubiquitously expressed in microenvironmental cells at the single-cell level, and its upregulation was associated with enhanced immune infiltration, cancer-associated fibroblast infiltration, and dysfunction of tumor-infiltrating cytotoxic T lymphocyte. Additionally, its expression was positively correlated with immune checkpoint genes, DNA mismatch repair genes, MSI (microsatellite instability) and TMB (tumor mutational burden) across various cancers. Its higher expression in cytotoxic T lymphocytes attenuated its ability to predict patient survival with PD-L1 (programmed death-ligand 1) blockade therapy, and FXYD5 was found to be a potential regulator of tumor immune escape and resistance to cancer immunotherapies. Based on GSEA (gene set enrichment analysis) and experimental verification, FXYD5 activated TGF‐β/SMAD signaling and drove EMT (epithelial-mesenchymal transition) to promote ovarian cancer progression. ConclusionIn summary, our study revealed that FXYD5-TGFβ axis may coregulate the interaction between tumors, CAFs (carcinoma-associated fibroblasts) and immune cells to reshape the tumor immune microenvironment and promote tumorigenesis and tumor progression. Thus, FXYD5 could be used as an immune-related biomarker for diagnosing and predicting the prognosis of multiple cancer types. Therefore, our findings suggest that targeting FXYD5 in TME (tumor microenvironment) may be a promising therapeutic strategy.

Functionalized biomimetic nanoparticles combining programmed death-1/programmed death-ligand 1 blockade with photothermal ablation for enhanced colorectal cancer immunotherapy.

Immune checkpoint blockade therapy targeting programmed death-1 (PD-1) or its major ligand programmed death-ligand 1 (PD-L1) has achievedremarkable success in the treatment of several tumors, including colorectal cancer. However, the efficacy of PD-1/PD-L1 inhibitors is limited in some colorectal cancers within the immunosuppressive tumor microenvironment (such as when there is a lack of immune cell infiltration). Herein, anti-PD-L1 functionalized biomimetic polydopamine-modified gold nanostar nanoparticles (PDA/GNS@aPD-L1 NPs) were developed for synergistic anti-tumor treatment by combining PD-1/PD-L1 blockade with photothermal ablation. PDA/GNS@aPD-L1 NPs were prepared by encapsulating photothermal nanoparticles (polydopamine-modified gold nanostar, PDA-GNS) with cell membrane isolated from anti-PD-L1 single-chain variable fragment (scFv) over-expressing cells. In addition to disrupting PD-1/PD-L1 immunosuppressive signals, the anti-PD-L1 scFv on the membrane of PDA/GNS@aPD-L1 NPs was conducive to the accumulation of PDA-GNS at tumor sites. Importantly, the tumor photothermal ablation induced by PDA-GNS could reverse the immunosuppressive tumor microenvironment, thereby further improving the efficiency of PD-1/PD-L1 blockade therapy. In this study, the synthetized PDA/GNS@aPD-L1 NPs exhibited good biocompatibility, efficient photothermal conversion ability, and enhanced tumor-targeting ability. In vivo studies revealed that a PDA/GNS@aPD-L1 NP-based therapeutic strategy significantly inhibited tumor growth, and prolonged overall survival by further promoting the maturation of dendritic cells (DCs), increasing the infiltration of CD8+T cells, and decreasing the number of immunosuppressive cells (such as regulatory T cells and myeloid-derived suppressive cells). Collectively, the developed PDA/GNS@aPD-L1 NP-based therapeutic strategy combines PD-1/PD-L1 blockade with photothermal ablation, which could remodel the tumor microenvironment for effective clinical colorectal cancer therapy. STATEMENT OF SIGNIFICANCE: Immunosuppressive tumor microenvironment is the main challenge facing programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) blockade therapy. By encapsulating photothermal nanoparticles (polydopamine-modified gold nanostar, PDA-GNS) with cell membrane over-expressing anti-PD-L1 single-chain variable fragment, we constructed anti-PD-L1 functionalized biomimetic nanoparticles (PDA/GNS@aPD-L1 NPs). By specific binding to the PD-L1 present on tumor cells, PDA/GNS@aPD-L1 NPs could disrupt PD-1/PD-L1 immunosuppression signaling, and effectively deliver PDA-GNS targeting to tumor sites. Additionally, PDA-GNS-mediated local photothermal ablation of tumors promoted the release of tumor-associated antigens and thus activated anti-tumor immune responses. Meanwhile, hyperthermia facilitates immune cell infiltration by increasing tumor vascular permeability. Therefore, PDA/GNS@aPD-L1 NPs could sensitize tumors to PD-1/PD-L1 blockade therapy by remodeling the immunosuppressive tumor microenvironment, which provides a new strategy for tumor treatment.

68Ga-HBED-CC-WL-12 PET in Diagnosing and Differentiating Pancreatic Cancers in Murine Models.

Positron emission tomography (PET) has been proven as an important technology to detect the expression of programmed death ligand 1 (PD-L1) non-invasively and in real time. As a PD-L1 inhibitor, small peptide WL12 has shown great potential in serving as a targeting molecule to guide PD-L1 blockade therapy in clinic. In this study, WL12 was modified with HBED-CC to label 68Ga in a modified procedure, and the biologic properties were evaluated in vitro and in vivo. 68Ga-HBED-CC-WL12 showed good stability in saline and can specifically target PD-L1-positive cells U87MG and PANC02. In PANC02-bearing mice, 68Ga-HBED-CC-WL12 showed fast permeation in subcutaneous tumors within 20 min (SUVmax 0.37) and was of higher uptake in 90 min (SUVmax 0.38). When compared with 18F-FDG, 68Ga-FAPI-04, and 68Ga-RGD, 68Ga-HBED-CC-WL12 also demonstrated great image quality and advantages in evaluating immune microenvironment. This study modified the 68Ga-labeling procedure of WL12 and obtained better biologic properties and further manifested the clinical potential of 68Ga-HBED-CC-WL12 for PET imaging and guiding for immunotherapy.

Single-Cell Analysis Reveals a CD4+ T-cell Cluster That Correlates with PD-1 Blockade Efficacy.

The identification of a new CD4+ T-cell metacluster that corresponds with immune status could guide effective tumor treatment by predicting response to immunotherapy using peripheral blood samples from patients.

Abstract 1345: p300/CBP bromodomain inhibitor CCS1477 enhances the efficacy of immune checkpoint blockade therapy in cancer treatment

Abstract Background: Blockade of programmed death-ligand 1 (PD-L1) by therapeutic antibodies has shown to be a promising strategy in cancer therapy, yet clinical response in many types of cancer is limited. Tumor cells secrete PD-L1 through exosomes or splice variants, which has been described as a new mechanism for the resistance to PD-L1 blockade therapy in multiple cancers. Our previous findings showed that the histone acetyltransferases p300/CBP could be recruited to the promoter of CD274 (encoding PD-L1) to regulate the expression of PD-L1. P300/CBP inhibition abrogated this process and reduced the secretion of exosomal PD-L1 by blocking the transcription of CD274, which combined with the anti-PD-L1 antibody to reactivate T cells function for tumor attack. In this study we have tested the outcome of combined immune checkpoint inhibitors with CCS1477, a novel p300/CBP bromodomain inhibitor, in pre-clinical models of prostate cancer and melanoma. Results: CCS1477 significantly decreased human prostate (DU145/PC-3) and melanoma (A375/SK-MEL-28) cancer cell line PD-L1 expression, as well as exosome secreted PD-L1 after 24 hours treatment. Moreover, consistent with these findings in vitro, CCS1477 (2.5mg//kg) also reduced PD-L1 expression in a syngeneic mouse prostate model (TRAMP-C2) and syngeneic mouse melanoma model (B16-F10). Meanwhile, CCS1477 treatment significantly increased tumor-infiltrating CD8+ and CD4+ T cells in syngeneic mouse models. Monotherapy treatment with CCS1477 or immune checkpoint inhibitors (anti-PD-L1 antibody for prostate cancer or anti-PD-L1 and anti-CTLA4 antibody for melanoma) resulted in significant but modest efficacy. Strikingly, the combination of immune checkpoint inhibitors with CCS1477 showed robust synergistic responses resulting in tumor regression. Mechanistically, CCS1477 treatment induced significant loss of H3K27 acetylation from super-enhancers of CD274, which subsequently induced a significant reduction of PD-L1 expression and exosome secreted-PD-L1. Also, we found that CCS1477 treatment significantly decreased the abundance of circulating and tumor-infiltrating myeloid-derived suppressor cells (MDSCs), which are known to play important roles in tumor immune evasion by inhibiting T cell’s activation. Reduction of MDSCs and exosome secreted-PD-L1 preserved T-cell function and elicited robust immunotherapy response combined with immune checkpoint blockade agents. Conclusions: These observations illuminate a clinically relevant hypothesis for combining CCS1477 with immune checkpoint blockade in the treatment of cancer. Citation Format: Jinghui Liu, Xinyi Wang, Katelyn Jones, Nigel Brooks, Neil Pegg, Xiaoqi Liu. p300/CBP bromodomain inhibitor CCS1477 enhances the efficacy of immune checkpoint blockade therapy in cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1345.

Macitentan improves antitumor immune responses by inhibiting the secretion of tumor-derived extracellular vesicle PD-L1.

Extracellular vesicles (EVs) carrying tumor cell-derived programmed death-ligand 1 (PD-L1) interact with programmed death 1 (PD-1)-producing T cells, thus significantly lowering a patient's response to immune checkpoint blockade drugs. No drug that reinvigorates CD8+ T cells by suppressing EV PD-L1 has been approved for clinical usage. Here we have identified macitentan (MAC), an FDA-approved oral drug, as a robust booster of antitumor responses in CD8+ T cells by suppressing tumor cell-derived EV PD-L1.Methods: EV was analyzed by the data from nanoparticle tracking, immunoblotting analyses, and nano-flow cytometry. Antitumor immunity was evaluated by luciferase assay and immune phenotyping using flow cytometry. Clinical relevance was analyzed using the cancer genome atlas database.Results: MAC inhibited secretion of tumor-derived EV PD-L1 by targeting the endothelin receptor A (ETA) in breast cancer cells and xenograft models. MAC enhanced CD8+ T cell-mediated tumor killing by decreasing the binding of PD-1 to the EV PD-L1 and thus synergizing the effects of the anti-PD-L1 antibody. MAC also showed an anticancer effect in triple-negative breast cancer (TNBC)-bearing immunocompetent mice but not in nude mice. The combination therapy of MAC and anti-PD-L1 antibody significantly improved antitumor efficacy by increasing CD8+ T cell number and activity with decreasing Treg number in the tumors and draining lymph nodes in TNBC, colon, and lung syngeneic tumor models. The antitumor effect of MAC was reversed by injecting exogenous EV PD-L1. Notably, ETA level was strongly associated with the innate anti-PD-1 resistance gene signature and the low response to the PD-1/PD-L1 blockade.Conclusion: These findings strongly demonstrate that MAC, already approved for clinical applications, can be used to improve and/or overcome the inadequate response to PD-1/PD-L1 blockade therapy.

IMMUNE REGULATORY FUNCTION OF INTERFERON-GAMMA IN ACUTE LEUKEMIA

Programmed death ligand-1 (PDL-1) is an immune regulatory component that is expressed on normal cells, tumor cells, and non-tumor immune cells. The expression of these checkpoint components on the cell surface helps prevent the immune system's overactivity. PDL-1 is associated with immune evasion in many solid tumors and lymphomas, while its clinical signicance is under exploration in leukemias. Structural and regulatory aspects are recently presented in reports that dene the role of signaling components in regulating PDL-1. Immune interactions of soluble cytokines such as IFN-γ & TNF-α with PDL1 show relevance in liquid malignancies. Recent reports have shown that interaction occurs between IFN- γ and PDL 1, but the exact mechanism is not dened. PDL1 expression around 20-25% across the malignancies has put this immune checkpoint in clinical trials, and many solid malignancies have shown better clinical outcomes and survival rates. Still, resistance remains a signicant hurdle. Immune resistance is the primary reason for the minimal impact of PDL-1 blockade therapy in various cancers. IFN-γ induced PDL1 immunotherapy could be effective in leukemias to overcome the resistance and provide effective immune responses and overall better clinical outcomes.

Programmed Death-Ligand 1 Expression in Breast Cancer Patients: Clinicopathological Associations from a Single-Institution Study.

PurposeTumor expression of programmed death-ligand 1 (PD-L1) is associated with evasion of immune response in several types of malignancies and such expression may render patients eligible for PD-L1 inhibitors. The use of immune checkpoint blockade therapy has been recently approved for the treatment of breast cancer. However, PD-L1 expression data are lacking among Jordanian breast cancer patients. In this study, the tumor PD-L1 expression was characterized in breast cancer patients to assess their eligibility for immune checkpoint blockade therapy. The study also aimed to explore the association between tumoral PD-L1 expression and the clinicopathologic characteristics and the prognostic factors in patients with breast cancer.Patients and MethodsTissue samples were available from 153 female patients with primary invasive breast cancer. Immunohistochemistry was performed on paraffin-embedded tumor sections that were stained with a PD-L1 antibody. Expression of tumor PD-L1 was correlated with demographics, clinicopathologic characteristics, and prognosis.ResultsThe mean age at diagnosis was 54.2±12.8 years (median 52, interquartile range 45–65). The percentage of PD-L1-positive tumors was 26.1%. PD-L1 expression on tumor cells significantly and positively correlated with tumor size (rho=0.174, p=0.032). PD-L1 positivity was significantly associated with the grade of carcinoma (p=0.001), HER2-positivity (p=0.015), and lymphovascular invasion (p=0.036). PD-L1 intensity was significantly associated with tumor stage (p=0.046). No significant associations were observed for the PD-L1 expression status or intensity with patient menopausal status, hormone receptor expression, and molecular subtypes. PD-L1 expression significantly correlated with a worse prognosis of breast cancer patients at the time of diagnosis (rho=0.230, p=0.005).ConclusionTumor PD-L1 expression was associated with advanced clinicopathologic features and worse prognosis in this cohort of Jordanian breast cancer patients. Future studies are needed to better understand the impact of PD-L1 blockade therapy on treatment outcomes in eligible breast cancer patients in Jordan.

Synergy between Toxoplasma gondii type I ΔGRA17 immunotherapy and PD-L1 checkpoint inhibition triggers the regression of targeted and distal tumors

BackgroundIn this study, we hypothesize that the ability of the protozoan Toxoplasma gondii to modulate immune response within the tumor might improve the therapeutic effect of immune checkpoint blockade. We...

Targeting Tim-3 in Cancer With Resistance to PD-1/PD-L1 Blockade.

Programmed death receptor 1 (PD-1) or programmed death ligand 1 (PD-L1) blocking therapy has completely changed the treatment pattern of malignant tumors. It has been tested in a wide range of malignant tumors and achieved clinical success. It might be a promising cancer treatment strategy. However, one of the important disadvantages of PD-1/PD-L1 blocking therapy is that only a few patients have a positive response to it. In addition, primary or acquired drug resistance can also lead to cancer recurrence in patients with clinical response. Therefore, it is very important to overcome the resistance of PD-1/PD-L1 blocking therapy and improve the overall response rate of patients to the immunotherapy. T cell immunoglobulin and mucin domain molecule 3 (Tim-3) belongs to the co-inhibitory receptor family involved in immune checkpoint function. Due to adaptive resistance, the expression of Tim-3 is up-regulated in PD-1/PD-L1 blocking therapy resistant tumors. Therefore, blocking the immune checkpoint Tim-3 might antagonize the resistance of PD-1/PD-L1 blocking therapy. This review systematically introduces the preclinical and clinical data of combined blockade of Tim-3 and PD-1/PD-L1 in cancer immunotherapy, and discusses the prospect of overcoming the drug resistance of PD-1/PD-L1 blockade therapy through blockade of Tim-3.

Immunotherapy in Treating EGFR-Mutant Lung Cancer: Current Challenges and New Strategies.

Lung cancer is the leading cause of cancer-related deaths worldwide. Immune checkpoint inhibitors, including monoclonal antibodies against programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1), have dramatically improved the survival and quality of life of a subset of non-small cell lung cancer (NSCLC) patients. Multiple predictive biomarkers have been proposed to select the patients who may benefit from the immune checkpoint inhibitors. EGFR-mutant NSCLC is the most prevalent molecular subtype in Asian lung cancer patients. However, patients with EGFR-mutant NSCLC show poor response to anti-PD-1/PD-L1 treatment. While small-molecule EGFR tyrosine kinase inhibitors (TKIs) are the preferred initial treatment for EGFR-mutant NSCLC, acquired drug resistance is severely limiting the long-term efficacy. However, there is currently no further effective treatment option for TKIs-refractory EGFR-mutant NSCLC patients. The reasons mediating the poor response of EGFR-mutated NSCLC patients to immunotherapy are not clear. Initial investigations revealed that EGFR-mutated NSCLC has lower PD-L1 expression and a low tumor mutational burden, thus leading to weak immunogenicity. Moreover, the use of PD-1/PD-L1 blockade prior to or concurrent with osimertinib has been reported to increase the risk of pulmonary toxicity. Furthermore, emerging evidence shows that PD-1/PD-L1 blockade in NSCLC patients can lead to hyperprogressive disease associated with dismal prognosis. However, it is difficult to predict the treatment toxicity. New biomarkers are urgently needed to predict response and toxicity associated with the use of PD-1/PD-L1 immunotherapy in EGFR-mutated NSCLC. Recently, promising data have emerged to suggest the potentiation of PD-1/PD-L1 blockade therapy by anti-angiogenic agents and a few other novel therapeutic agents. This article reviews the current investigations about the poor response of EGFR-mutated NSCLC to anti-PD-1/PD-L1 therapy, and discusses the new strategies that may be adopted in the future.

Efficacy and Feasibility of Programmed Death-1/Programmed Death Ligand-1 Blockade Therapy in Non-Small Cell Lung Cancer Patients With High Antinuclear Antibody Titers.

BackgroundImmune checkpoint inhibitor (ICI) therapy has been described to markedly improve patient survival. However, reports describing the antitumor therapeutic efficacy and safety of ICIs in patients with autoantibodies are scarce.MethodsThis study examined the efficacy and feasibility of ICIs in antinuclear antibody (ANA)-positive patients with non-small cell lung cancer (NSCLC). An ANA titer greater than 1:40 and 1:80 was defined as positive and high, respectively. Patients who were treated with ICIs at Saitama Medical University, International Medical Center between January 2016 and December 2018 were retrospectively reviewed.ResultsOne hundred and nineteen of the 266 patients (44.7%) who received nivolumab, pembrolizumab, and atezolizumab had positive ANA titers. Their median age was 69 (range, 39–84) years. The overall response rate of the ANA-positive patients was 35.9% (37/103), which was not less than that of the ANA-negative group. The median progression-free survival in the ANA-positive group was 6.3 months versus 4.3 months in the ANA-negative group (p = 0.08). Twenty-seven ANA-positive patients (10.2%) had high ANA titers. However, ICI efficacy was not decreased in these patients. Regardless of the cutoff of ANA titers (1:40 or 1:80), the rate of patients who experienced adverse events were not significantly different between the two groups.ConclusionThe administration of ICIs to ANA-positive patients has clinical benefits. The prevalence of adverse events in the ANA-positive group was not higher than that in the ANA-negative group.

PD0325901, an ERK inhibitor, enhances the efficacy of PD-1 inhibitor in non-small cell lung carcinoma

ERK pathway regulated the programmed death ligand-1 (PD-L1) expression which was linked to the response of programmed death-1 (PD-1)/PD-L1 blockade therapy. So it is deducible that ERK inhibitor could enhance the efficacy of PD-1 inhibitor in cancer immunotherapy. In this study, PD0325901, an oral potent ERK inhibitor, strongly enhanced the efficacy of PD-1 antibody in vitro and in vivo models in non-small cell lung carcinoma (NSCLC) cells. Mechanistically, PD0325901 or shRNA-ERK1/2 significantly downregulated the PD-L1 expression in NSCLC cells and increased the CD3+ T cells infiltration and functions in tumor tissue. There was a positive correlation between the p-ERK1/2 expression and PD-L1 expression in patients with NSCLC. And the patients with low p-ERK1/2 expression were observed a high response rate of PD-1/PD-L1 blockage therapy. Our results demonstrate that PD0325901, an ERK inhibitor, can enhance the efficacy of PD-1 blockage against NSCLC in vitro and in vivo models. And the combination of ERK inhibitor such as PD0325901 and PD-1/PD-L1 blockage is a promising regimen and encouraged to be further confirmed in the treatment of patients with NSCLC.

Comparison of PD-L1 immunohistochemical assays and the significance of PD-L1 expression in thymoma.

Thymoma is a relatively rare malignancy, which is categorized as thymic epithelial tumor but known as the most common pathology that is developed in the anterior mediastinum. Complete resection is recommended for localized tumors and usually favorable prognosis can be obtained. However, poor survival period has been reported in unresectable cases exhibiting extensive invasion or distant metastasis, as effective chemotherapeutic regimens are restrained. We previously assessed expression of programmed death ligand 1 (PD-L1) and programmed death 1 (PD-1) and discussed their prospective application in the immunotherapy of thymic epithelial tumors. After our publication, additional studies using reliable PD-L1 antibodies, which are currently administered to predict efficacy of PD-1/PD-L1 blockade therapy were performed and further characterized PD-L1 in thymoma. Herein, recent knowledge in relation to the significance of PD-L1 expression in thymoma is reviewed based on recent findings using qualified PD-L1 clones. Most studies coherently found high expression of PD-L1 on the cell membrane and cytoplasm of tumor epithelial cells in accordance with previous reports, which is a predictive marker for effectiveness of anti-PD-1/PD-L1 drugs, even when approved PD-L1 antibodies were employed. On the other hand, PD-L1 expression on tumor infiltrating immune cells remains to be sufficiently determined. High PD-L1 expression can be expected in cases with high grade histological subtypes, such as type B2/B3 thymomas, or those with advanced stages III or IV of the disease. Interestingly, the level of PD-L1 expression was found to be upregulated after chemotherapy compared with that before, which could be explained by immunogenic cell death. The prognostic impact of PD-L1 expression in thymoma might be found only when thymic carcinoma patients were excluded. Furthermore, it also could be identified when we analyzed thymomas completely resected, distinct from biopsy and incompletely resected cases.

Nuclear imaging-guided PD-L1 blockade therapy increases effectiveness of cancer immunotherapy

ObjectivesStrategies to improve the responsiveness of programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) checkpoint blockade therapy remain an essential topic in cancer immunotherapy. In this study, we developed a new radiolabeled...

P300/CBP inhibition enhances the efficacy of programmed death-ligand 1 blockade treatment in prostate cancer.

Blockade of programmed death-ligand 1 (PD-L1) by therapeutic antibodies has shown to be a promising strategy in cancer therapy, yet clinical response in many types of cancer, including prostate cancer (PCa), is limited. Tumor cells secrete PD-L1 through exosomes or splice variants, which has been described as a new mechanism for the resistance to PD-L1 blockade therapy in multiple cancers, including PCa. This suggests that cutting off the secretion or expression of PD-L1 might improve the response rate of PD-L1 blockade therapy in PCa treatment. Here we report that p300/CBP inhibition by a small molecule p300/CBP inhibitor dramatically enhanced the efficacy of PD-L1 blockade treatment in a syngeneic model of PCa by blocking both the intrinsic and interferon gamma (IFN-γ)-induced PD-L1 expression. Mechanistically, p300/CBP could be recruited to the promoter of CD274 (encoding PD-L1) by the transcription factor IRF-1, which induced the acetylation of Histone H3 at CD274 promoter followed by the transcription of CD274. A485, a p300/CBP inhibitor, abrogated this process and cut off the secretion of exosomal PD-L1 by blocking the transcription of CD274, which combined with the anti-PD-L1 antibody to reactivate T cells function for tumor attack. This finding reports a new mechanism of how cancer cells regulate PD-L1 expression through epigenetic factors and provides a novel therapeutic approach to enhance the efficacy of immune checkpoint inhibitors treatment.

Multi-layered control of PD-L1 expression in Epstein-Barr virus-associated gastric cancer.

Gastric cancer (GC) is the fifth most common cancer worldwide. In approximately 10% of GC cases, cancer cells show ubiquitous and monoclonal Epstein-Barr virus (EBV) infection. A significant feature of EBV-associated GC (EBVaGC) is high lymphocytic infiltration and high expression of immune checkpoint proteins, including programmed death-ligand 1 (PD-L1). This highlights EBVaGC as a strong candidate for immune checkpoint blockade therapy. Indeed, several recent studies have shown that EBV positivity in GC correlates with positive response to programmed cell death protein 1 (PD-1)/PD-L1 blockade therapy. Understanding the mechanisms that control PD-L1 expression in EBVaGC can indicate new predictive biomarkers for immunotherapy, as well as therapeutic targets for combination therapy. Various mechanisms have been implicated in PD-L1 expression regulation, including structural variations, post-transcriptional control, oncogenic activation of intrinsic signaling pathways, and increased sensitivity to extrinsic signals. This review provides the most recent updates on the multilayered control of PD-L1 expression in EBVaGC.

Management of Adverse Events in Cancer Patients Treated With PD-1/PD-L1 Blockade: Focus on Asian Populations.

The interaction between programmed cell death protein 1 (PD-1) and its ligand programmed death-ligand 1 (PD-L1) induces exhaustions of cytotoxic lymphocytes in the tumor microenvironment, which facilitates tumor immune evasion. PD-1/PD-L1 blockade therapy, which prevents the receptors and ligands from binding to each other, disrupts the T-cell exhaustion signaling, thereby increasing antitumor immunity. Inspiringly, it has revolutionized the treatment of many different types of cancers including non-small-cell lung carcinoma, melanoma, lymphoma, and so on. However, with the intention of generating an antitumor immune response, PD-1/PD-L1 blockade may also lead to a spectrum of side effects. The profile of adverse events (AEs) of PD-1/PD-L1 blockade is not exactly the same with other immune checkpoint blockades, such as blockade of cytotoxic T-lymphocyte-associated protein 4. Although cutaneous, gastrointestinal, and pulmonary systems are common victims, AEs of PD-1/PD-L1 blockade might occur in any other organ system of the human body. These toxicities can be life-threatening if not managed promptly, and proper treatment intervention is imperative for optimal control and prevention of severe damage. Currently, clinical practice for the management of AEs in PD-1/PD-L1 blockade remains sporadic and variable. The majority of initial clinical trials were carried out in Caucasians. The trials of multiple races usually included a small portion of Asian participants, and results were calculated and interpreted for the entire included subjects without any race-specific conclusions. Therefore, the information on PD-1/PD-L1 blockade in Asians is far from systematic or comprehensive. Recently, as the results of clinical trials of anti-PD-1/PD-L1 agents in Asian populations have been gradually released, we summarized current evidence with a specific focus on the Asian population, hoping to outline strategies and offer guidance on the management of AEs in cancer patients treated with PD-1/PD-L1 blockade in the Asian world.

Association of PD-L1 protein expression and TMB in non-small cell lung cancer.

e20009 Background: Programmed death-ligand 1 (PD-L1) protein expression and tumor mutation burden (TMB) are considered to be two of the most promising biomarkers for predicting response to PD-1/PD-L1 blockade therapy. To evaluate the association of PD-L1 expression and TMB in non-small cell lung cancer (NSCLC), we designed a study to compare PD-L1 expression levels and TMB values from the same FFPE samples. Methods: 153 NSCLC patients were enrolled between August 2018 and January 2019. An FFPE sample with at least 10 sections was taken from each patient. DNA was extracted from half of the FFPE sections, and was sequenced using a 605 gene panel to 5,000× depth. In silico analysis was conducted to compare the TMB value obtained using this 605-gene panel with that determined using whole exome sequencing (WES). The Pearson rank correlation of TMBs determined using the 605 gene panel versus those using WES was 0.9379, indicating results of the two methods are highly consistent. The other halves of the FFPE sections were used to evaluate PD-L1 expression using immunohistochemical (IHC) techniques. Because WES is considered the gold standard for determining TMB, we re-analyzed WES sequencing data obtained from all 1049 NSCLC patient samples in the TCGA database, and demonstrated that the TMB determined using the 605 gene panel was highly consistent with that obtained using WES. Results: We determined that 22.22% (34/153) of samples had high PD-L1 expression (defined as > 50% of cells being PD-L1 positive), but their TMB values varied from 0.76 to 19.84. The correlation between PD-L1 expression and TMB was only 0.154, indicating that PD-L1 expression had no significant association with TMB. Conclusions: PD-L1 expression and TMB are both important biomarkers for PD-L1 therapy. Many patients were only tested for either PD-L1 expression or TMB due to cost and sample limitations. The results of our study suggest that both PD-L1 and TMB should be examined in NSCLC patients.

Programmed Death Ligand 1 (PD-L1) Expression in Epithelial Ovarian Cancer: A Comparison of Type I and Type II Tumors

Objective:To examine the expression of programmed death ligand 1 (PD-L1) in type I and type II epithelial ovarian cancers (EOC) and its associations with outcomes. Methods:Records of 132 women with EOC were reviewed. Immunostaining of PD-L1 was performed with formalin-fixed, paraffin-embedded specimens. Expression of PD-L1 was classified into four categories (0; 1+; 2+; 3+) according to intensity of expression. Expression of PD-L1 ≥2+ was deemed to be high. Results:Of the 132 women, 75 (56.8%) and 57 (43.2%) women had type I and type II tumors, respectively. Approximately 70% of cases exhibited high PD-L1 expression. There was no significant difference in the rate of high PD-L1 expression between the two EOC types (65.3% versus 59.6%). In type I tumors, high PD-L1 expression was associated with more advanced stages (51.0% versus 34.6%), greater recurrence (46.9% versus 26.9%), and shorter median progression-free survival (27 months versus 62 months) than low expression. In type II tumors, there were no apparent differences between high and low expression of PD-L1 in terms of the percentage of advanced-stage tumors (82.6% versus 79.4%), recurrence (56.5% versus 58.8%), and median progression-free survival (21 months versus 24 months). Conclusion:high PD-L1 expression is associated with worse oncological outcomes in type I EOC. This finding emphasizes the merit of further studies to confirm this promising result and to determine the potential role of PD-L1 blockade therapy in type I EOC.