2024 World Conference on Lung Cancer (WCLC) - Posters-P2.11A.21 CCL4 Attenuated the Efficacy of Immunotherapy via Regulating the Phenotype and Function of Treg in EGFR-TKI Resistant NSCLC

P2.11A.21 CCL4 Attenuated the Efficacy of Immunotherapy via Regulating the Phenotype and Function of Treg in EGFR-TKI Resistant NSCLC

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This study investigated how the chemokine CCL4 affects the efficacy of immune checkpoint inhibitors (ICIs) in non-small-cell lung cancer (NSCLC) patients with resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). The authors conducted a retrospective analysis of patients treated between 2016 and 2021, highlighting a poorer response in those with acquired resistance to EGFR-TKI therapy. Using single-cell sequencing and flow cytometry, they explored the tumor microenvironment, finding significant discrepancies between patients with primary versus acquired resistance.<br /><br />One major finding was the increased expression of CCL4 in tumor cells of patients with acquired EGFR-TKI resistance. This chemokine was shown to modulate the phenotype and function of regulatory T cells (Tregs), notably upregulating CD39 on Tregs, which impacted CD8 T cell cytotoxicity. Experiments demonstrated that supplementing CCL4 increased CD39 expression and decreased the production of IFN-γ and granzyme B by CD8 T cells, thereby attenuating their cytotoxic function. This suppression could be counteracted by anti-CD39 inhibitors in vitro.<br /><br />The authors concluded that EGFR-TKI-resistant NSCLC tumor cells secrete CCL4, modifying Treg activity in a way that undermines CD8 T cell function, ultimately impeding the effectiveness of anti-PD-(L)1 immunotherapy. This highlights a potential mechanistic pathway that could be targeted to improve immunotherapy outcomes in these patients. The research suggests that addressing CCL4-mediated immune regulation might enhance therapeutic responses for patients with acquired resistance to EGFR-TKIs.

Asset Subtitle

Sangtian Liu

Meta Tag

Speaker Sangtian Liu

Topic Metastatic NSCLC – Immunotherapy

Keywords

CCL4

immune checkpoint inhibitors

non-small-cell lung cancer

EGFR-TKI resistance

tumor microenvironment

regulatory T cells

CD39

CD8 T cells

anti-PD-(L)1 immunotherapy

immune regulation