A comprehensive analysis of the correlation between plasma cytokines/chemokines and tumor immune microenvironment signature influences the response of checkpoint inhibitors in advanced non-small-cell lung cancer

Abstract

Objectives: Circulating cytokines/chemokines are linked to checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC). The tumor-immune microenvironment (TIME) plays a significant role in modulating a broad range of cytokines and chemokines. This study aimed to explore the crosstalk between circulating cytokines/chemokines and TIME, related to ICIs outcomes. Methods: We conducted a prospective cohort study of 81 participants with advanced or recurrent NSCLC who received ICIs. Pretreatment comprehensive 27 cytokines/chemokines analysis, immunohistochemistry (IHC) for CD8, Treg/FOXP3, and PD-L1(22C3) TPS, and RNA sequencing were conducted. Demographic characteristics were integrated in the analysis to define the crosstalk of significant TIME-related signatures. Circulating neutrophil-to-lymphocyte ratio (NLR) and IHC tumor-infiltrated neutrophil density were evaluated to correlate systemic and local inflammatory states with ICIs response. Results: Pretreatment plasma IL-6 and IL-8 were the significant cytokines correlated with surrogate ICIs responses and ICIs progression-free survival (PFS). Despite several correlations between cytokines/chemokines and CD8⁺ TILs, Treg/FOXP3⁺ TILs, neither pretreatment IL-6 nor IL-8 was correlated with intra-tumoral or stromal Treg/FOXP3⁺ TILs, CD8⁺ TILs, and PD-L1. Four active neutrophil-related gene signatures overlapped and were significantly correlated with better ICIs outcomes and lower IL-6 levels. Among 69 genes in 4 neutrophil-related gene signatures, the overexpression of TREM1, SORL1, and HSD17B11 significantly contributed and inversely correlated with CIBERSORT memory B cells. Clinically, the stratification by low levels of IL-6/IL-8 and low NLR identified a subgroup with significantly improved survival outcomes, whereas IHC tumor-infiltrated neutrophil counts did not show a similar association. Conclusion: Our study reveals a potential mechanistic axis linking circulating IL-6 and IL-8 to tumor-associated neutrophils, memory B cells, and therapeutic response. These findings underscore the crucial role of synergistic treatment in augmenting the efficacy of ICIs. The crosstalk between neutrophils and B cells in the orchestration of ICIs therapy for NSCLC was further elucidated through the roles of HSD17B11, SORL1, and TREM1.