Soluble immune checkpoint factors reflect exhaustion of antitumor immunity and response to PD-1 blockade
Hidetoshi Hayashi, … , Kazuhiko Nakagawa, Tasuku Honjo
Hidetoshi Hayashi, … , Kazuhiko Nakagawa, Tasuku Honjo
Published April 1, 2024
Citation Information: J Clin Invest. 2024;134(7):e168318. https://doi.org/10.1172/JCI168318.
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Clinical Research and Public Health Oncology

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

Abstract

BACKGROUND Precise stratification of patients with non–small cell lung cancer (NSCLC) is needed for appropriate application of PD-1/PD-L1 blockade therapy.METHODS We 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.RESULTS Nonresponsiveness 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.CONCLUSION Combinations 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 REGISTRATION UMIN000019674.FUNDING This study was funded by Ono Pharmaceutical Co. Ltd. and Sysmex Corporation.

Authors

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

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Figure 3

Soluble immune factors complement the predictive ability of tPD-L1 expression for advanced NSCLC patients treated with nivolumab in the Nivolution trial.

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Soluble immune factors complement the predictive ability of tPD-L1 expre...
(A–C) Pearson correlation analysis for pretreatment plasma concentrations of sPD-L1 (A), sPD-1 (B), sCTLA-4 (C), and tPD-L1 expression level (PD-L1 TPS) (n = 50). (D–F) Comparison of sPD-L1 (D), sPD-1 (E), and sCTLA-4 (F) concentrations between patients with a DCB (n = 10) or NCB (n = 27) among individuals with a tPD-L1 expression level of < 50%. *P < 0.05 (Mann-Whitney U test). (G–I) Kaplan-Meier curves for PFS of patients with a tPD-L1 expression level of < 50% according to high or low levels of each soluble immune factor based on the determined cutoff values. For sPD-L1 (high, n = 21; low, n = 16), median PFS was 8.7 versus 2.7 months for low and high sPD-L1, respectively (log-rank P = 0.001), with an HR of 0.30 (95% CI, 0.14–0.64) (G). For sPD-1 (high, n = 20; low, n = 17), median PFS was 7.8 versus 2.4 months for low and high sPD-1, respectively (log-rank P = 0.003), with an HR of 0.34 (95% CI, 0.16–0.71) (H). For sCTLA-4 (high, n = 14; low, n = 23), median PFS was 7.1 versus 2.4 months for low and high sCTLA-4, respectively (log-rank P = 0.004), with an HR of 0.36 (95% CI, 0.17–0.75) (I). (J–L) Kaplan-Meier curves for PFS of patients with a tPD-L1 expression level of ≥ 50% according to high or low levels of each soluble immune factor based on the determined cutoff values. For sPD-L1 (high, n = 8; low, n = 5), median PFS was not reached versus 11.0 months for low and high sPD-L1, respectively (log-rank P = 0.023), with an HR of 0.01 (95% CI, 0.00–19.61) (J). For sPD-1 (high, n = 8; low, n = 5), median PFS was 5.7 months versus not reached for low and high sPD-1, respectively (log-rank P = 0.49), with an HR of 1.88 (95% CI, 0.31–11.32) (K). For sCTLA-4 (high, n = 7; low, n = 6), median PFS was not reached versus 12.7 months for low and high sCTLA-4, respectively (log-rank P = 0.16), with an HR of 0.23 (95% CI, 0.03–2.14) (L). (M and N) Kaplan-Meier curves for PFS among patients with tPD-L1 expression levels of < 50% (M) or ≥ 50% (N) according to the number of favorable immune factors defined as sCTLA-4 or sPD-L1 concentrations below the cutoff values (log-rank P = 0.0002 and 0.18, respectively). Median PFS was 5.1, 2.2, and 1.4 months for 2, 1, and 0 favorable factors, respectively, in (M), and not reached, not reached, and 11.0 months, respectively, in (N). The HR for 1 (n = 11 and 3) versus 0 (n = 12 and 6) was 0.28 (95% CI, 0.10–0.76) and 0.44 (95% CI, 0.05–3.97), and that for 2 (n = 14 and 4) versus 0 was 0.20 (95% CI, 0.10–0.76) and 0.01 (95% CI, 0.00–45.45), in (M) and (N), respectively.