Cisplatin and Gemcitabine Exert Opposite Effects on Immunotherapy With PD-1 Antibody in K-Ras-Driven Cancer

Authors

Christophe Glorieux
Xiaojun Xia
Xin You
Zining Wang
Yi Han
Jing Yang
Gauthier Noppe
Christophe de Meester
Jianhua Ling
Annie Robert
Hui Zhang
Sheng-Ping Li
Huamin Wang
Paul J Chiao
Li Zhang
Xiaobing Li
Peng Huang

Publication Date

9-1-2022

Journal

Journal of Advanced Research

Abstract

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

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.

Keywords

Animals, Antineoplastic Agents, B7-H1 Antigen, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Cisplatin, Deoxycytidine, Humans, Immunologic Factors, Immunotherapy, Lung Neoplasms, Mice, Programmed Cell Death 1 Receptor, Proto-Oncogene Proteins p21(ras), Gemcitabine, K-ras, Cisplatin, Gemcitabine, PD-1/PD-L1, Immunochemotherapy

Comments

Supplementary Materials

PMID: 36100320