Abstract 2851: EGFR-TKI drives the reprogramming of CD8+ T cell immunity in non-small cell lung cancer

Abstract Non-small cell lung cancer (NSCLC), the most common type of lung cancer, remains the leading cause of cancer-related deaths globally. Although different cancer-driving mutations have been reported in NSCLC, their prevalence varies across ethnic groups. Among Asian patients, EGFR mutations have been reported to be the most prevalent. EGFR tyrosine kinase inhibitors (EGFR-TKI) are applied to NSCLC patients carrying EGFR mutations, although EGFR-TKIs are effective treatments, their potential impact on the immune system remains largely unknown. Understanding the interactions between EGFR-TKIs and immune regulation is crucial for developing combination therapy strategies. In this study, we demonstrated that EGFR-TKI suppresses the activation, proliferation, and effector cytokine production of CD8+ T cells. Moreover, in therapeutic models, EGFR-TKI treatment negatively impacts the antitumor response of CD8+ T cells. Notably, when EGFR-TKIs were combined with anti-PD-1 therapy, tumor growth was increased compared with anti-PD-1 monotherapy, indicating that EGFR-TKIs may diminish the efficacy of immune-checkpoint blockade. In parallel with our findings in mouse models, studies of NSCLC patients who underwent EGFR-TKI also showed decreased CD8+ T cell activation and IFNγ production. Moreover, we identified potential EGFR-TKI-interacting targets in T cells and found that EGFR-TKIs bind to actin-interacting proteins, thereby disrupting cytoskeletal organization and compromising T-cell function. Together, these results reveal an EGFR-independent mechanism through which EGFR-TKIs attenuate CD8+ T-cell antitumor activity. In conclusion, our findings not only suggest a suppression effect of EGFR-TKI on CD8+ T cells but also provide crucial information on developing EGFR-TKI combination strategies with immunotherapies for NSCLC patients. Citation Format: Ssu-Pei Yu, Hao-Chen Chi, Meng-Yun Lin, Chao-Chi Ho, Geen-Dong Chang, Ming-Shyue Lee, Chun-Jung Ko. EGFR-TKI drives the reprogramming of CD8+ T cell immunity in non-small cell lung cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2851.