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 6

Analysis of gene expression in peripheral CD8+ T cells and circulating cytokine levels.

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Analysis of gene expression in peripheral CD8+ T cells and circulating c...
(A) Volcano plots of Pearson correlation (x-axis) and significance (y-axis) for the expression of individual genes in peripheral CD8+ T cells as determined by microarray analysis and pretreatment plasma concentrations of sPD-L1, sPD-1, or sCTLA-4 in cohort B (validation cohort, n = 40 patients). (B) Enrichment analysis for genes whose expression was positively correlated with sPD-L1 (447 genes) or sPD-1 (611 genes) levels as shown in A at P values of < 0.001. The plots show the FDR (q) value (x-axis), adjusted P value (dot size), and gene counts (color). The number of correlated genes for sCTLA-4 was not sufficient for enrichment analysis. (C) Heat map of Pearson correlation between soluble immune factor concentrations and the expression of gene sets characteristic of naive, progenitor exhausted, or terminally exhausted CD8+ T cells as determined by microarray analysis as in A. (D) Correlation between the plasma concentrations of 30 cytokines as well as those of sPD-L1, sPD-1, and sCTLA-4 in 50 patients of cohort A (Nivolution trial). Hierarchical clustering was performed according to the concentrations of the cytokines and soluble immune factors. (E) Scatter plots of soluble immune factor levels and the frequency of PD-1hi CD8+ T cells in peripheral blood (n = 84 from cohorts B and C). A moderate correlation between sPD-1 levels and the frequency of PD-1hi CD8+ T cells was apparent, with an R value of 0.51 and P < 0.0001; the gray shaded area above and below the solid line and bounded by the dotted lines indicates the 95% CI.