CCL20 Released by Drug-Tolerant Persisters Impairs Immunotherapy in EGFR-Mutated Lung Adenocarcinoma

ABSTRACT: EGFR-mutated lung adenocarcinoma (LUAD) often shows suboptimal response to immune checkpoint inhibitors (ICIs), attributed to an immunosuppressive tumor immune microenvironment (TIME). Drug-tolerant persisters (DTPs), a subpopulation of cancer cells that can survive initial therapy, contribute to this resistance by releasing CCL20, a chemokine that fosters tumor immune privilege. This preclinical study aims to explore the role of CCL20 in modulating TIME and its impact on ICI efficacy in EGFR-mutated LUAD. We utilized a humanized mouse model engrafted with EGFR-mutated NCI-H1975 LUAD cells and human peripheral blood mononuclear cells (PBMCs) to mimic a human immune system. Mice were treated with anti-PD-1, anti-CCL20, or a combination of both. Xenograft growth was monitored, and resected xenograft were analyzed using single-cell RNA sequencing (scRNA-seq) and multiplex immunofluorescence microscopy to assess changes in tumor cell transcriptional profiles and immune cell infiltration including. Results demonstrated that anti-PD-1 or anti-CCL20 monotherapy showed minimal effects on tumor growth, their combination significantly suppressed tumor progression and CCL20 expression in DTP subpopulations and altered the transcriptional profile of tumor cells. Combined treatment also reduced hypoxia-related genes and appeared to enhance stress response pathways. In addition, the combined treatment enhanced infiltration of immune cells, shifting the TIME toward an immunogenic state. In conclusion, co-inhibition of CCL20 and PD-1 remodels the TIME, overcoming ICI resistance in EGFR-mutated LUAD. These findings suggest that targeting CCL20 alongside PD-1 blockade could enhance immunotherapy efficacy, offering a novel therapeutic strategy for this patient population.

ORGANISM(S): Homo sapiens

PROVIDER: GSE293914 | GEO | 2026/08/12

REPOSITORIES: GEO