Abstract
BACKGROUND: Immune checkpoint blockade (ICB) has been improving patient outcomes of non-small cell lung cancer (NSCLC), but its effectiveness is highly subjective to individual tumor microenvironment. As dominant immune cells in NSCLC, tumor-associated macrophages (TAMs) display high diversity and plasticity. This study aims to find crucial TAM subtypes associated with ICB response in NSCLC. MATERIALS AND METHODS: Large cohorts of NSCLC patients from The Cancer Genome Atlas and a single-cell sequencing dataset were integrated to illustrate immunosuppressive phenotypes of TAMs, followed by experimental verification. 341 NSCLC surgical samples and 40 tissue samples of NSCLC patients who received ICB treatment were collected to state the clinical importance of TAMs. RESULTS: We identified a TREM2 positive ((+)) TAM subtype in NSCLC stratifying patient responses to immunotherapy. NSCLC patients with high TREM2(+) TAM infiltration exhibited advanced tumor progression, inferior prognosis and unique NSCLC molecular characteristics, especially mutations of EGFR. TREM2(+) TAMs were induced in TME, but not existed in peripheral blood. TREM2(+) TAMs were enriched with multiple anti-inflammatory cytokines, exhibiting a M2-like immunosuppressive phenotype, and potentiate T cell dysfunction including impaired anti-tumor activity of CD8(+) T cells and enhanced differentiation towards FOXP3(+) Tregs, thus facilitating immune evasion of NSCLC. Response rates to PD-1-based ICB were higher in patients with low TREM2(+) TAMs (31.58%) compared to high TREM2(+) TAMs (14.29%). CONCLUSIONS: Our findings implicated the immunosuppressive role of TREM2(+) TAMs in NSCLC, and systematically reveal the clinical significance of TREM2(+) TAMs as predictive and prognostic markers for NSCLC patients with ICB treatment.