PD-L1: Biological mechanism, function, and immunotherapy in gastric cancer.
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ABSTRACT:
SUBMITTER: Zhang Y
PROVIDER: S-EPMC9729722 | biostudies-literature | 2022
REPOSITORIES: biostudies-literature
Publications
PD-L1: Biological mechanism, function, and immunotherapy in gastric cancer.
Zhang Yingzi Y Yang Yan Y Chen Yiran Y Lin Wu W Chen Xiangliu X Liu Jin J Huang Yingying Y Wang Haiyong H Teng Lisong L
Frontiers in immunology 20221124
Gastric cancer (GC) is one of the main causes of cancer incidence rate and mortality worldwide. As the main breakthrough direction, the application of immune checkpoint inhibitors makes patients with GC have better prognosis, where PD-L1/PD-1 inhibitors in immunotherapy have good anti-tumor immune efficacy. Further understanding of the regulatory mechanism of PD-L1 in GC may bring substantial progress to the immunotherapy. In this review, we provide information on the endogenous and exogenous re ...[more]
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Project description:BackgroundImmune checkpoint inhibitors (ICI) are now standard-of-care treatment for patients with metastatic gastric cancer (GC). To guide patient selection for ICI therapy, programmed death ligand-1 (PD-L1) biomarker expression is routinely assessed via immunohistochemistry (IHC). However, with an increasing number of approved ICIs, each paired with a different PD-L1 antibody IHC assay used in their respective landmark trials, there is an unmet clinical and logistical need for harmonization. We investigated the interchangeability between the Dako 22C3, Dako 28-8 and Ventana SP-142 assays in GC PD-L1 IHC.MethodsIn this cross-sectional study, we scored 362 GC samples for PD-L1 combined positive score (CPS), tumor proportion score (TPS) and immune cells (IC) using a multiplex immunohistochemistry/immunofluorescence technique. Samples were obtained via biopsy or resection of gastric cancer.ResultsThe percentage of PD-L1-positive samples at clinically relevant CPS ≥ 1, ≥ 5 and ≥ 10 cut-offs for the 28-8 assay were approximately two-fold higher than that of the 22C3 (CPS ≥ 1: 70.3 vs 49.4%, p < 0.001; CPS ≥ 5: 29.1 vs 13.4%, p < 0.001; CPS ≥ 10: 13.7 vs 7.0%, p = 0.004). The mean CPS score on 28-8 assay was nearly double that of the 22C3 (6.39 ± 14.5 vs 3.46 ± 8.98, p < 0.001). At the clinically important CPS ≥ 5 cut-off, there was only moderate concordance between the 22C3 and 28-8 assays.ConclusionOur findings suggest that scoring PD-L1 CPS with the 28-8 assay may result in higher PD-L1 scores and higher proportion of PD-L1 positivity compared to 22C3 and other assays. Until stronger evidence of inter-assay concordance is found, we urge caution in treating the assays as equivalent.
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Project description:BackgroundThe programed death ligand-1 combined positive score (PD-L1 CPS), the only FDA-approved biomarker for immune checkpoint inhibitor therapy in gastric cancer (GC) patients, is an important but imperfect predictive biomarker. The molecular characteristics of tumors that influence the PD-L1 CPS are largely unknown and would be helpful for screening patients who would benefit from immunotherapy.MethodsPD-L1 immunohistochemistry (IHC) and targeted next-generation sequencing techniques were used to compare genomic alterations in 492 GC patients in two groups (PD-L1 CPS ⩾ 1, positive; CPS < 1, negative). Screened PD-L1 expression-related factors were analyzed for immunotherapy efficacy in three distinct GC cohorts from public databases.ResultsPositive PD-L1 expression occurred in 40% of GC patients and was associated with a higher proportion of phosphatidylinositol 3-kinase (PI3K), SWItch/Sucrose NonFermentable (SWI/SNF), lysine demethylase (KDM), and DNA (cytosine-5)-methyltransferase (DNMT) (all p < 0.01), pathway alterations. Compared to wild-type GC patients, those with PI3K pathway alterations had a higher response rate (p = 0.002) and durable clinical benefit rate with immunotherapy (p = 0.023, p = 0.038) as well as longer progression-free survival (p = 0.084, p = 0.0076) and overall survival (p = 0.2, p = 0.037) with immunotherapy.ConclusionThis study revealed PD-L1 expression-related factors in the tumor genome in a GC cohort. Alterations in the PI3K pathway associated with PD-L1 positivity were shown to be associated with better immunotherapy efficacy in three distinct GC cohorts from public databases. Our results provide a potential avenue for patient selection and rational immune combination development for GC patients.
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Project description:Several cancers are highly refractory to conventional chemotherapy. The survival of tumors in several cases is assisted by checkpoint immunomodulation to maintain the imbalance between immune surveillance and cancer cell proliferation. Check point antibody inhibitors, such as anti-PD-1/PD-L1, are a novel class of inhibitors that function as a tumor suppressing factor via modulation of immune cell-tumor cell interaction. These checkpoint blockers are rapidly becoming a highly promising cancer therapeutic approach that yields remarkable antitumor responses with limited side effects. In recent times, more than four check point antibody inhibitors have been commercialized for targeting PD-1, PDL-1, and CTLA-4. Despite the huge success and efficacy of the anti-PD therapy response, it is limited to specific types of cancers, which attributes to the insufficient and heterogeneous expression of PD-1 in the tumor microenvironment. Herein, we review the current landscape of the PD-1/PD-L1 mechanistic role in tumor immune evasion and therapeutic outcome for cancer treatment. We also review the current progress in clinical trials, combination of drug therapy with immunotherapy, safety, and future of check point inhibitors for multiple types of cancer.
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Project description:BackgroundImmunotherapy dramatically changed the treatment landscape of gastric cancer in recent years. PD-L1 expression was proposed as a biomarker; however, the treatment strategy according to PD-L1 is still uncertain. Here, we aimed to find the appropriate cutoff value of PD-L1 expression for gastric cancer immunotherapy.MethodsWe did a systematic electronic research of prospective clinical trials of gastric cancer immunotherapy across databases. Studies that provided subgroup analysis results stratified by PD-L1 expression were included. Objective response rate (ORR), disease control rate (DCR), hazard ratio (HR), and 95% confidential interval (CI) of progression-free survival (PFS) and overall survival (OS) at different PD-L1 cutoff values were extracted.ResultsTwelve studies and 6,488 patients in total were finally included for pooled analysis. ORR in allover, PD-L1-negative, combined positive score (CPS) ≥1, CPS ≥5, and CPS ≥10 population was 10%, 3%, 13%, 20%, and 23%, respectively. Immune checkpoint inhibitor (ICI) monotherapy failed to show survival advantage in allover and PD-L1-negative patients. Single-agent ICI therapy prolonged OS (HR = 0.84, 95% CI: 0.74-0.96) but not PFS (HR = 1.38, 95% CI: 0.91-2.09) in PD-L1 CPS ≥1 patients. For combined immunotherapy, ORR in allover, PD-L1-negative, CPS ≥1, CPS ≥5, and CPS ≥10 population was 64%, 57%, 48%, 60%, and 58%, respectively. Allover population could gain survival benefit from combined immunotherapy based on the results from Checkmate-649. OS (HR = 0.81, 95% CI: 0.71-0.92) and PFS (HR = 0.77, 95% CI: 0.69-0.86) were significantly prolonged in PD-L1 CPS ≥1 patients receiving combined immunotherapy.ConclusionEfficacy and survival advantages improved with PD-L1 CPS. CPS ≥1 was the cutoff value for ICI monotherapy to gain survival benefit. Combined immunotherapy prolonged PFS and OS in allover population but needs further study to confirm it.
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Project description:Programmed death-ligand 1 (PD-L1) plays an essential role in tumor cell escape from anti-tumor immunity in various types of cancer, including gastric cancer (GC). The present study investigated the intracellular and membrane-bound expression of PD-L1 in the GC cell lines MKN1, MKN74, KATO III and OCUM-1. Furthermore, soluble PD-L1 (sPD-L1) level in the supernatant of GC cells and the serum of patients with GC and healthy controls was determined by ELISA. Interferon (IFN)-? treatment of cells resulted in increased cytoplasmic expression of PD-L1 in GC cells in a dose-dependent manner, except for MKN74 cells; however, there was no association between tumor necrosis factor-? treatment and enhanced PD-L1 expression. Concordant with these findings, results from flow cytometry analysis demonstrated that membrane-bound PD-L1 expression was also increased following GC cell treatment with IFN-? in a dose-dependent manner. In addition, significant sPD-L1 overproduction was observed only in the culture supernatant of OCUM-1 cells. Serum level of sPD-L1 was significantly increased in patients with GC, in particular in stage IV patients, compared with healthy controls. In conclusion, the present study demonstrated that IFN-? treatment increased the intracellular and membrane-bound PD-L1 expression in GC cells. In addition, sPD-L1 was detected not only in the supernatant of GC cells but also in the serum of patients with GC. Further investigation on the underlying mechanism of regulation of PD-L1 expression and sPD-L1 production is required.
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