1. Soluble immune checkpoint factors reflect exhaustion of antitumor immunity and response to PD-1 blockade.
- Author
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Kurosaki, Takashi, Togashi, Yosuke, Fukuoka, Kazuya, Goto, Megumi, Chiba, Yasutaka, Tomida, Shuta, Ota, Takayo, Haratani, Koji, Takahama, Takayuki, Tanizaki, Junko, Yoshida, Takeshi, Iwasa, Tsutomu, Tanaka, Kaoru, Takeda, Masayuki, Hirano, Tomoko, Yoshida, Hironori, Ozasa, Hiroaki, Sakamori, Yuichi, Sakai, Kazuko, Higuchi, Keiko, Uga, Hitoshi, Suminaka, Chihiro, Hirai, Toyohiro, Nishio, Kazuto, Nakagawa, Kazuhiko, Honjo, Tasuku, Hayashi, Hidetoshi, Chamoto, Kenji, and Hatae, Ryusuke
- Subjects
Immunotherapy ,Lung cancer ,Oncology ,T cells ,Humans ,B7-H1 Antigen ,Carcinoma ,Non-Small-Cell Lung ,Immunologic Factors ,Lung Neoplasms ,Programmed Cell Death 1 Receptor ,Immune Checkpoint Inhibitors - Abstract
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.
- Published
- 2024