Soluble immune checkpoint factors reflect exhaustion of antitumor immunity and response to PD-1 blockade
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
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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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 2

Combination of circulating soluble immune factors allows stratification of patients with advanced NSCLC in the Nivolution trial according to responsiveness to nivolumab.

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Combination of circulating soluble immune factors allows stratification ...
(A–C) Comparison of pretreatment plasma concentrations of sPD-L1 (A), sPD-1 (B), and sCTLA-4 (C) between patients with a DCB (n = 20) or NCB (n = 30). Mean ± SD values are indicated; Mann-Whitney U test. (D–F) Kaplan-Meier curves for PFS of patients with high or low concentrations of each soluble immune factor based on the determined cutoff values. For D, the sPD-L1 cutoff was 205 pg/mL (high, n = 29; low, n = 21), and the median PFS was 9.1 versus 2.2 months for low and high sPD-L1, respectively (log-rank P = 0.002), with an HR of 0.35 (95% CI, 0.18–0.68). For E, the sPD-1 cutoff was 135 pg/mL (high, n = 26; low, n = 24), and the median PFS was 5.2 versus 2.8 months for low and high sPD-1, respectively (log-rank P = 0.459), with an HR of 0.78 (95% CI, 0.41–1.50). For F, the sCTLA-4 cutoff was 1.85 pg/mL (high, n = 21; low, n = 29), and the median PFS was 5.7 versus 2.7 months for low and high sCTLA-4, respectively (log-rank P = 0.074), with an HR of 0.54 (95% CI, 0.27–1.06). (G) Kaplan-Meier curves for PFS among patients according to the number of favorable immune factors defined as sCTLA-4 or sPD-L1 levels below the cutoff values (log-rank P = 0.015). Median PFS was 14.1, 4.5, and 1.5 months for 2, 1, and 0 favorable factors, respectively. The HR for 1 (n = 14) versus 0 (n = 18) was 0.72 (95% CI, 0.34–1.53), and that for 2 (n = 18) versus 0 was 0.31 (95% CI, 0.14–0.72).