Priming PD-L1 expression by chemotherapeutic agents in non-small cell lung cancers.

Abstract

e20087 Background: Immunotherapy targeting PD-1/PD-L1 axis has yielded fruitful results in non-small cell lung cancers (NSCLCs). Evidences showed that treatment responses are likely correlated with tumor PD-L1 expression levels, which is especially true in the first line setting. Results from Keynote-021 suggested that pembrolizumab plus platinum-pemetrexed doublet came out with better overall response rate and progression free survival as compared to chemotherapy alone even in the PD-L1 low-expression group. Nevertheless, grade III and IV toxicities were much frequently observed in the combinational arm. The aim of the current study is to investigate the effect of chemotherapeutics on PD-L1 priming in NSCLCs so as to provide a better option in the chemo-immunotherapy combinational setting. Methods: NSCLC cell lines CL1-5, CL141, and H1299 were treated with a platinum-based drug (cisplatin), microtubule-targeted agents (paclitaxel or vinorelbine), or antimetabolites (pemetrexed or gemcitabine) for 24 to 72 hrs. The concentration of each drug selected for experiments was stepping-down titrated from the IC50s, with the maximum concentration allowed being 10 μM. The priming effects of chemotherapeutics on PD-L1 expression were evaluated with RT-qPCR, Immunoblotting and FACSCalibur flow cytometer. The functionality of the induced PD-L1 was examined by the T cell cytotoxic assay and the IL-2 production ability, done with co-cultured systems containing chemo-primed tumor cells and activated T cells. Results: The results showed that pemetrexed or gemcitabine, but not cisplatin, paclitaxel or vinorelbine, effectively induced PD-L1 expression at concentrations below the IC50s. Membranous distribution of the induced PD-L1 was observed. Addition of anti-PD-L1 blocking antibody in the co-cultured system increased T cell cytotoxic ability and promoted IL-2 production, implicating the biological functionality of the induced PD-L1. Conclusions: The data suggested that pemetrexed or gemcitabine effectively primed the expression of biologically functional PD-L1 in NSCLC cells. The results implicate that pemetrexed or gemcitabine alone may be a good combinational candidate for PD-L1-targeted therapy in NSCLCs.

Programmed Cell Death Ligand 1 in Breast Cancer: Technical Aspects, Prognostic Implications, and Predictive Value

“…In particular, it has recently been shown that PD‐L1 significantly increased on residual disease after NACT compared with baseline in a large retrospective cohort of patients with TN early BC . The induction of PD‐L1 expression by chemotherapy is consistent with observations in other cancer types and with the notion that chemotherapy is able to induce an adaptive immune response through various mechanisms, including immunogenic cell death and the activation of the damage response c‐GAS/STING . Indeed, it has been shown that CT may boost the immunogenicity of the tumor by increasing tumor immune infiltrate from baseline to post‐NACT samples, with a high rate of conversion from low‐TIL to high‐TILs tumor .…”

In situ formed reactive oxygen species–responsive scaffold with gemcitabine and checkpoint inhibitor for combination therapy

“…Previous reports showed that prior chemotherapy enhanced the therapeutic outcome of immunotherapy (18)(19)(20)(21)(22), which also reversed chemoresistance after prolonged chemotherapy (20,23). Although some chemotherapeutic drugs have modest activity when used as single treatments, their combination with immunotherapy may result in enhanced anticancer effects and can be used to promote an immunogenic tumor phenotype (24)(25)(26). In addition, engineered delivery vehicles and scaffolds are increasingly considered as promising tools for transporting immunotherapeutics (27)(28)(29)(30)(31)(32)(33), with decreased systemic toxicities.…”

A Multifunctional Biomimetic Nanoplatform for Relieving Hypoxia to Enhance Chemotherapy and Inhibit the PD‐1/PD‐L1 Axis

“…However, those blockade therapy still suffer from low immune response rate because of low neoantigen burden and tumor immunogenicity . Based on this problem, previous researches showed that chemotherapy could strengthen the effects of immunotherapy, which in reverse reduced chemoresistanse after long‐term chemotherapy . Although chemotherapy has modest effects when served as single treatments, their synergy with immunotherapy may provide enhanced antitumor effects because of immunogenic cell death (ICD) induced by chemotherapy …”