1. NLRP4 negatively regulates type I interferon response and influences the outcome in anti-programmed cell death protein (PD)-1/PD-ligand 1 therapy.
- Author
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Wang H, Xia L, Yao CC, Dong H, Yang Y, Li C, Ji WX, Sun RM, Duan HQ, Mengzhou W, Xia WM, Wang SJ, Ji P, Li Z, Jiao L, Wang Y, and Lu S
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Animals, CD8-Positive T-Lymphocytes drug effects, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung immunology, Cell Line, Tumor, Female, Humans, Immune Checkpoint Inhibitors pharmacology, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms immunology, Lymphocytes, Tumor-Infiltrating drug effects, Macrophages drug effects, Male, Mice, Middle Aged, Mutation, Progression-Free Survival, Signal Transduction drug effects, Treatment Outcome, Tumor Microenvironment drug effects, Tumor Microenvironment immunology, Adaptor Proteins, Signal Transducing metabolism, B7-H1 Antigen antagonists & inhibitors, Immune Checkpoint Inhibitors therapeutic use, Interferon Type I metabolism, Programmed Cell Death 1 Receptor antagonists & inhibitors
- Abstract
The challenge to improve the clinical efficacy and enlarge the population that benefits from immune checkpoint inhibitors (ICIs) for non-small-cell lung cancer (NSCLC) is significant. Based on whole-exosome sequencing analysis of biopsies from NSCLC patients before anti-programmed cell death protein-2 (PD-1) treatment, we identified NLRP4 mutations in the responders with a longer progression-free survival (PFS). Knockdown of NLRP4 in mouse Lewis lung cancer cell line enhanced interferon (IFN)-α/β production through the cGAS-STING-IRF3/IRF7 axis and promoted the accumulation of intratumoral CD8
+ T cells, leading to tumor growth retardation in vivo and a synergistic effect with anti-PD-ligand 1 therapy. This was consistent with clinical observations that more tumor-infiltrating CD8+ T cells and elevated peripheral IFN-α before receiving nivolumab treatment were associated with a longer PFS in NSCLC patients. Our study highlights the roles of tumor-intrinsic NLRP4 in remodeling the immune contextures in the tumor microenvironment, making regional type I IFN beneficial for ICI treatment., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)- Published
- 2022
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