WCLC 2025 - Posters & ePosters-P2.02.08 A Unique VEGFA-Expressing CAF Subpopulation Emerges in TKI-Resistant Lung Cancer to Mediate Immunotherapy Sensitization and Adverse Outcomes

P2.02.08 A Unique VEGFA-Expressing CAF Subpopulation Emerges in TKI-Resistant Lung Cancer to Mediate Immunotherapy Sensitization and Adverse Outcomes

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This study investigates the tumor microenvironment (TME) in EGFR-mutant lung cancer, focusing on resistance to tyrosine kinase inhibitors (TKIs) and the response to immunotherapy. EGFR-TKI resistance remains a major challenge in treating EGFR-mutant lung cancer patients. Notably, immunotherapy exhibits superior efficacy in patients who have developed TKI resistance compared to TKI-naive patients, but the mechanisms underlying this difference are unclear.<br /><br />Using single-cell sequencing of lung cancer biopsies from EGFR wild-type, EGFR-mutant, and TKI-resistant patients, the researchers identified a unique subpopulation of cancer-associated fibroblasts (CAFs) characterized by high expression of VEGFA, termed VEGF_CAFs. Among various VEGFA-expressing cells in the TME, only CAF-derived VEGFA was significantly reduced in EGFR-mutant patients and further diminished after TKI resistance. This suggests VEGF_CAFs may play a role in modulating tumor sensitivity to immunotherapy post-TKI resistance.<br /><br />The study further validated the presence of VEGF_CAFs through multicolor immunofluorescence and flow cytometry in both human and mouse tumors. To explore VEGF_CAFs' functional role, a murine fibroblast cell line overexpressing VEGFA was generated. Co-implantation of these VEGF_CAFs with lung cancer cells in mice promoted tumor growth, implying their tumor-supportive role.<br /><br />Overall, these findings reveal that VEGF_CAFs emerge in the TME of TKI-resistant lung cancers, contributing to adverse prognosis yet potentially sensitizing tumors to immunotherapy. This mechanistic insight may explain the improved efficacy of immunotherapy in TKI-resistant cases and offers new therapeutic avenues to overcome EGFR-TKI resistance by targeting this fibroblast subpopulation.

Asset Subtitle

Jingze Wang

Meta Tag

Speaker Jingze Wang

Topic Tumor Biology – Preclinical Biology

Keywords

EGFR-mutant lung cancer

tumor microenvironment

tyrosine kinase inhibitor resistance

immunotherapy response

cancer-associated fibroblasts

VEGFA expression

VEGF_CAFs

single-cell sequencing

tumor growth

therapeutic targets