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INTRODUCTION

Immunochemotherapy using PD-1/PD-L1 antibodies in combination with chemotherapeutic agents has become a mainstream treatment for cancer patients, but it remains unclear which drug combinations would produce best therapeutic outcome.

OBJECTIVES

The purpose of this study was to investigate two common chemotherapeutic drugs, gemcitabine and cisplatin, for their impacts on the therapeutic efficacy of PD-1 antibody in K-ras-driven cancers known to overexpress PD-L1.

METHODS

Both in vitro assays and syngeneic mouse tumor models were used in this study. Biochemical and molecular assays were used to determine the effects of drugs on T cell functions in cell culture models and in mouse/human tumor tissues. Allograft tumor models with K-ras mutation were used to investigate the combination effect of gemcitabine or cisplatin with immunotherapy. Data of lung cancer patients with K-ras mutation treated with cisplatin and toripalimab were analyzed to evaluate the clinical relevance of the lab findings.

RESULTS

Cisplatin and gemcitabine unexpectedly exert opposite effect on the therapeutic activity of PD-1 antibody in vivo. Gemcitabine antagonizes the therapeutic effect of PD-1 antibody due to its significant inhibition on CD8 T cell infiltration, which was observed both in mouse tumor allografts and in human pancreatic cancer tissues. In contrast, cisplatin shows synergistic activity with PD-1 antibody by activation of CD8 T cells through the DNA damage-mediated cGAS-STING sensing mechanism, leading to increase of T cell infiltration and secretion of antitumor cytokines. Clinical data show that a combination of cisplatin with PD-1 antibody toripalimab could be effective in advanced lung cancer patients with K-ras mutation who failed prior therapies.

CONCLUSIONS

Our study shows that a key factor in selecting chemotherapeutic agents for immunochemotherapy is the drug's impact on T cell functions, and that cisplatin-based chemotherapy is an excellent choice for combination with immune checkpoint antibody to achieve favorable clinical outcome.

简介

使用 PD-1/PD-L1 抗体的免疫化疗与化疗药物联合使用已成为癌症患者的主流治疗方法，但哪种药物组合能产生最佳治疗效果仍不清楚。

目的

本研究旨在研究两种常见的化疗药物——吉西他滨和顺铂，它们对已知过度表达 PD-L1 的 K-ras 驱动型癌症中 PD-1 抗体治疗效果的影响。

方法

本研究采用了体外检测和同基因小鼠肿瘤模型。生化和分子检测用于确定药物在细胞培养模型和小鼠/人肿瘤组织中对 T 细胞功能的影响。使用带有 K-ras 突变的同种异体移植肿瘤模型来研究吉西他滨或顺铂与免疫治疗的联合效应。分析了 K-ras 突变的肺癌患者接受顺铂和特瑞普利单抗治疗的数据，以评估实验室发现的临床相关性。

结果

出乎意料的是，顺铂和吉西他滨在体内对 PD-1 抗体的治疗活性产生相反的影响。吉西他滨通过显著抑制 CD8 T 细胞浸润来拮抗 PD-1 抗体的治疗效果，这在小鼠肿瘤同种异体移植和人胰腺肿瘤组织中均有观察到。相比之下，顺铂通过 DNA 损伤介导的 cGAS-STING 感应机制激活 CD8 T 细胞，与 PD-1 抗体表现出协同作用，导致 T 细胞浸润增加和抗肿瘤细胞因子的分泌。临床数据表明，在先前治疗失败的 K-ras 突变晚期肺癌患者中，顺铂联合 PD-1 抗体特瑞普利单抗可能有效。