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. 2024 Sep 5;73(11):214.
doi: 10.1007/s00262-024-03781-8.

Characterization of pre- and on-treatment soluble immune mediators and the tumor microenvironment in NSCLC patients receiving PD-1/L1 inhibitor monotherapy

Daiki Murata  1 , Koichi Azuma  2 , Kenta Murotani  3 , Akihiko Kawahara  4 , Yuuya Nishii  1 , Takaaki Tokito  1 , Tetsuro Sasada  5 , Tomoaki Hoshino  1
Affiliations

Characterization of pre- and on-treatment soluble immune mediators and the tumor microenvironment in NSCLC patients receiving PD-1/L1 inhibitor monotherapy

Daiki Murata et al. Cancer Immunol Immunother. .

Abstract

Background: Despite the favorable therapeutic efficacy observed with ICI monotherapy, the majority of non-small cell lung cancer (NSCLC) patients do not respond. Therefore, identifying patients who could optimally benefit from ICI treatment remains a challenge.

Methods: Among 183 patients with advanced or recurrent NSCLC who received ICI monotherapy, we analyzed 110 patients whose pre- and post-treatment plasma samples were available. Seventy-three soluble immune mediators were measured at ICI initiation and 6 weeks later. To identify useful biomarkers, we analyzed the association of pre-treatment levels and on-treatment changes of soluble immune mediators with survival of patients. The associations of pre-treatment or on-treatment biomarkers with irAE development, PD-L1 expression, CD8+ TIL density, and neutrophil to lymphocyte ratio (NLR) were also analyzed.

Results: Univariate analysis showed that pre-treatment biomarkers included 6 immune mediators, whereas on-treatment biomarkers included 8 immune mediators. Multivariate analysis showed that pre-treatment biomarkers included 4 immune mediators (CCL19, CCL21, CXCL5, CXCL10), whereas on-treatment biomarkers included 5 immune mediators (CCL7, CCL19, CCL23, CCL25, IL-32). IrAE development was associated with on-treatment change in CCL23. PD-L1 expression was associated with the pre-treatment levels of TNFSF13B and the on-treatment change in CCL25. CD8+ TIL density was associated with the pre-treatment CXCL10 level, whereas NLR was correlated with pre-treatment levels of CCL13 and CCL17.

Conclusion: We identified several soluble immune mediators as pre-treatment and on-treatment biomarkers of survival in patients with NSCLC treated with ICI monotherapy. Some of these biomarkers were associated with other possible predictors, including irAE development, PD-L1 expression, CD8+ TIL density and NLR. Further large-scale studies are needed to establish biomarkers for patients with NSCLC who received ICI monotherapy.

Keywords: Biomarker; CD8+ TILs; Chemokine; Cytokine; Immune checkpoint inhibitor; NSCLC.

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Conflict of interest statement

KA reports receiving personal fees from AstraZeneca, MSD, Bristol Myers Squibb, Ono Pharmaceutical, Takeda Pharmaceutical, Pfizer, and Chugai Pharmaceutical. TT reports receiving personal fees from AstraZeneca, Bristol Myers Squibb, MSD, Novartis, and Chugai Pharmaceutical. TS reports receiving personal fees from Chugai Pharmaceutical and Bristol Myers Squibb, and research funds from Taiho, and BrightPath Biotherapeutics. The remaining authors have no conflicts of interest to disclose.

Figures

Fig. 1
Fig. 1
A Overview of the study. We analyzed 110 patients for whom pre- and post-treatment plasma samples were available. Plasma samples were collected at ICI initiation and 6 weeks later. A multiplex assay was used to measure plasma levels of 73 soluble immune mediators. The associations between the 73 immune mediators and patient prognosis were analyzed. B Flow diagram of the study population. Among the 183 patients with advanced or recurrent NSCLC who received ICI monotherapy, we analyzed 110 patients whose pre- and post-treatment plasma samples were available. C Kaplan–Meier survival curves for PFS and OS. The median PFS was 2.8 months (95%CI: 2.2–4.7), and the median OS was 11.9 months (95%CI: 8.2–14.7). 95%CI: 95% confidence interval, ICI: immune checkpoint inhibitor, PFS: progression-free survival, OS: overall survival
Fig. 2
Fig. 2
Heatmap showing the associations of patient survival with pre-treatment biomarkers, irAE development, PD-L1 expression and CD8+ TIL density. The p values represent the results of univariate analysis for each pre-treatment biomarker. The colors of the pre-treatment biomarkers were classified in a four-tier scale. The cu-toff level was the quartile point for each pre-treatment biomarker. Patients with any grade irAE or Grade > 3 irAE are also colored. PD-L1 expression was categorized as < 1% and > 1% for evaluable patients. CD8+ TIL density was categorized into high and low groups based on median values. For evaluable patients, PD-L1 expression and CD8+ TIL density are shown in two colors. irAE: immune-related adverse event, PD-L1: programmed cell death ligand-1, TILs: tumor-infiltrating lymphocytes
Fig. 3
Fig. 3
On-treatment changes in soluble immune mediators associated with patient survival. For each patient, increased on-treatment changes are indicated by orange bars and decreased on-treatment changes are indicated by blue bars. The p values represent the results of univariate analysis for each on-treatment biomarker
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