CCL5 在 NSCLC 中协调矛盾的免疫景观：同时招募效应细胞和抑制细胞塑造免疫治疗耐药

Background: The chemokine CCL5 exhibits a complex role in cancer immunotherapy, yet its dual immunomodulatory functions in non-small cell lung cancer (NSCLC) remain poorly understood. Methods and Results: Based on a newly analyzed clinical cohort of 33 advanced NSCLC patients receiving anti-PD-1 therapy combined with platinum-based chemotherapy, we found that elevated baseline peripheral blood CCL5 levels significantly predicted shorter overall survival (27. 6 months vs. not reached, HR = 2. 779, p = 0. 038) and a higher incidence of immune-related pneumonitis ( p = 0. 0072). These clinical observations were supported by the re-analysis of a previously published single-cell RNA sequencing (scRNA-seq) dataset ( n = 8), which indicated that high CCL5 expression in peripheral blood T/NK cells was associated with a lower major pathological response ( p = 0.

029). To explore the underlying mechanisms, we conducted detailed analyses using a large, publicly available tumor scRNA-seq dataset (GSE243013, n = 234). These analyses revealed that high intratumoral CCL5 simultaneously promoted the recruitment of both immune effector cells (CD8 + T cells, NK cells) and immunosuppressive populations (Tregs, MDSCs). This paradoxical immune landscape correlated with elevated immune checkpoint expression and significantly higher TIDE scores (1.

47 vs. 0. 83, p < 0. 001). CellChat and SCENIC network analyses identified intensified T cell-myeloid communication and key transcription factors (e. g. , FOXP3, EOMES) mediating this dichotomy. Conclusions: This hypothesis-generating study raises the possibility that CCL5 orchestrates paradoxical immune responses and may serve as a biomarker in NSCLC.

Further validation in larger prospective, independent cohorts is required.