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
View: Text | PDF
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

×

Figure 5

Soluble immune factors efficiently stratify patients with hot tumors in the Nivolution trial.

Options: View larger image (or click on image) Download as PowerPoint
Soluble immune factors efficiently stratify patients with hot tumors in ...
(A and B) Comparison of pretreatment plasma concentrations of sPD-L1, sPD-1, or sCTLA-4 between patients with a DCB or NCB among individuals with hot (A) or cold (B) tumors defined by the number of CD8+ T cells infiltrated into tumor tissue (≥ 12.0 and < 12.0/field, respectively). DCB, n = 14 and 5; NCB, n = 10 and 18 for hot and cold tumors, respectively. *P < 0.05; Mann-Whitney U test. (C–E) Kaplan-Meier curves for PFS according to hot or cold tumor status and high or low soluble factor levels based on the determined cutoff values. For sPD-L1, 2-sided log-rank P = 0.0023 for comparison among the 4 groups, where n = 11 (sPD-L1 low) and 13 (sPD-L1 high) among hot tumors as well as n = 9 (low) and 14 (high) among cold tumors; and median PFS was not reached, 2.2 months, 2.8 months, and 1.9 months, respectively (C). For sPD-1, 2-sided log-rank P = 0.055; n = 9 (sPD-1 low) and 15 (sPD-1 high) among hot tumors as well as n = 12 (low) and 11 (high) among cold tumors; and median PFS was not reached, 5.6 months, 2.7 months, and 1.5 months, respectively (D). For sCTLA-4, 2-sided log-rank P = 0.0093; n = 12 (sCTLA-4 low) and 12 (sCTLA-4 high) among hot tumors as well as n = 14 (low) and 9 (high) among cold tumors; and median PFS was not reached, 4.9 months, 2.8 months, and 1.5 months, respectively (E). (F and G) Kaplan-Meier curves for PFS of patients with hot (F) or cold (G) tumors according to the number of favorable immune factors defined as concentrations of sCTLA-4 or sPD-L1 below the cutoff values (2-sided log-rank P = 0.0034 and 0.30, respectively). Median PFS was not reached, 4.3 months, and 4.1 months for 2, 1, and 0 favorable factors, respectively, for hot tumors (F), and was 2.8, 5.7, and 1.5 months, respectively, for cold tumors (G). The HR for 1 (n = 7 and 5) versus 0 (n = 9 and 9) was 0.85 (95% CI, 0.29–2.44) and 0.46 (95% CI, 0.13–1.57), and that for 2 (n = 8 and 9) versus 0 was 0.07 (95% CI, 0.01–0.55) and 0.58 (95% CI, 0.21–1.56), for hot and cold tumors, respectively. (H–J) Pearson correlation analysis of tumor burden and plasma concentrations of sPD-L1 (H), sPD-1 (I), or sCTLA-4 (J) for hot (red) and cold (blue) tumors. Hot tumors in H show moderate linearity, with an R of 0.59 and P = 0.004. The red shaded area above and below the solid line and bounded by the dotted lines indicates the 95% CI.