Journal Article

Soluble immune checkpoint factors reflect exhaustion of antitumor immunity and response to PD-1 blockade

Chiba, Yasutaka, Togashi, Yosuke, Suminaka, Chihiro, Tanizaki, Junko, Ota, Takayo, Haratani, Koji, Yoshida, Hironori, Kurosaki, Takashi, Takahama, Takayuki, Uga, Hitoshi, Yoshida, Takeshi, Hatae, Ryusuke, Fukuoka, Kazuya, Hirano, Tomoko, Hayashi, Hidetoshi, Higuchi, Keiko, Honjo, Tasuku, Sakai, Kazuko, Tomida, Shuta, Nakagawa, Kazuhiko, Nishio, Kazuto, Hirai, Toyohiro, Chamoto, Kenji, Takeda, Masayuki, Goto, Megumi, Iwasa, Tsutomu, Ozasa, Hiroaki, Tanaka, Kaoru, Sakamori, Yuichi

2024

Overview

BACKGROUNDPrecise stratification of patients with non-small cell lung cancer (NSCLC) is needed for appropriate application of PD-1/PD-L1 blockade therapy.METHODSWe measured soluble forms of the immune-checkpoint molecules PD-L1, PD-1, and CTLA-4 in plasma of patients with advanced NSCLC before PD-1/PD-L1 blockade. A prospective biomarker-finding trial (cohort A) included 50 previously treated patients who received nivolumab. A retrospective observational study was performed for patients treated with any PD-1/PD-L1 blockade therapy (cohorts B and C), cytotoxic chemotherapy (cohort D), or targeted therapy (cohort E). Plasma samples from all patients were assayed for soluble immune-checkpoint molecules with a highly sensitive chemiluminescence-based assay.RESULTSNonresponsiveness to PD-1/PD-L1 blockade therapy was associated with higher concentrations of these soluble immune factors among patients with immune-reactive (hot) tumors. Such an association was not apparent for patients treated with cytotoxic chemotherapy or targeted therapy. Integrative analysis of tumor size, PD-L1 expression in tumor tissue (tPD-L1), and gene expression in tumor tissue and peripheral CD8+ T cells revealed that high concentrations of the 3 soluble immune factors were associated with hyper or terminal exhaustion of antitumor immunity. The combination of soluble PD-L1 (sPD-L1) and sCTLA-4 efficiently discriminated responsiveness to PD-1/PD-L1 blockade among patients with immune-reactive tumors.CONCLUSIONCombinations of soluble immune factors might be able to identify patients unlikely to respond to PD-1/PD-L1 blockade as a result of terminal exhaustion of antitumor immunity. Our data suggest that such a combination better predicts, along with tPD-L1, for the response of patients with NSCLC.TRIAL REGISTRATIONUMIN000019674.FUNDINGThis study was funded by Ono Pharmaceutical Co. Ltd. and Sysmex Corporation.

• Publisher: American Society for Clinical Investigation
• Subject: Analysis / Antitumor activity / B cells / B7-H1 Antigen / Biological markers / Biomarkers / Cancer / Cancer therapies / Carcinoma, Non-Small-Cell Lung - drug therapy / Carcinoma, Non-Small-Cell Lung - genetics / Carcinoma, Non-Small-Cell Lung - pathology / Care and treatment / CD8 antigen / Cell death / Chemiluminescence / Chemotherapy / Clinical Medicine / CTLA-4 protein / Cytotoxicity / Diagnosis / Gene expression / Health aspects / Humans / Immune checkpoint / Immune Checkpoint Inhibitors - pharmacology / Immune Checkpoint Inhibitors - therapeutic use / Immune response / Immunity / Immunity (Disease) / Immunologic Factors - blood / Immunologic Factors - chemistry / Immunotherapy / Ipilimumab / Lung cancer / Lung cancer, Non-small cell / Lung Neoplasms - drug therapy / Lung Neoplasms - genetics / Lung Neoplasms - pathology / Lymphocytes / Lymphocytes T / Medical research / Medicine, Experimental / Monoclonal antibodies / Non-small cell lung carcinoma / Oncology / PD-1 protein / PD-L1 protein / Plasma / Programmed Cell Death 1 Receptor / Small cell lung carcinoma / T cells / Targeted cancer therapy / Tumors