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<p>Adoptive T&#xa0;cell therapy has shown significant efficacy in cancer treatment, especially in hematologic malignancies, and is increasingly being explored for solid cancers. Combining T&#xa0;cell therapy with conventional treatments holds promise for enhancing therapeutic effects. In this study, we conducted an in vitro inhibitor screening to evaluate the effects of various inhibitors on T cell-mediated cytotoxic activity against cancer cells. Among the candidates, we identified afatinib as an immunosuppressive agent that attenuates T&#xa0;cell cytotoxic activity by reducing interferon-<i>γ</i> (IFN-<i>γ</i>) secretion and suppressing T&#xa0;cell activation. Notably, this IFN-<i>γ</i> reduction was independent of T&#xa0;cell proliferation. RNA-seq analysis revealed that afatinib downregulated the T&#xa0;cell receptor (TCR) pathway signature. RT-qPCR demonstrated a dose-dependent suppression of <i>IFNG</i> mRNA expression in afatinib-treated T cells. Furthermore, afatinib impaired tumor rejection in an immunological memory mouse model&#xa0;that had been previously cured by anti–PD-L1 therapy, suggesting that afatinib may inhibit the function of effector memory T cells. Collectively, our findings highlight afatinib’s potential to impair T&#xa0;cell effector functions, indicating that strategic consideration is essential when combining epidermal growth factor receptor–tyrosine kinase&#xa0;inhibitors (EGFR-TKIs), including afatinib, with adoptive T&#xa0;cell therapies.</p>

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Afatinib exerts an inhibitory effect on T cell-mediated cytotoxicity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月3日

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  • Masaru Yokomura,
  • Seiji Nagano,
  • Hiroshi Kawamoto,
  • Yoshihiko Hirohashi,
  • Toshihiko Torigoe,
  • Takahiro Asakage,
  • Ryohei Katayama

摘要

Adoptive T cell therapy has shown significant efficacy in cancer treatment, especially in hematologic malignancies, and is increasingly being explored for solid cancers. Combining T cell therapy with conventional treatments holds promise for enhancing therapeutic effects. In this study, we conducted an in vitro inhibitor screening to evaluate the effects of various inhibitors on T cell-mediated cytotoxic activity against cancer cells. Among the candidates, we identified afatinib as an immunosuppressive agent that attenuates T cell cytotoxic activity by reducing interferon-γ (IFN-γ) secretion and suppressing T cell activation. Notably, this IFN-γ reduction was independent of T cell proliferation. RNA-seq analysis revealed that afatinib downregulated the T cell receptor (TCR) pathway signature. RT-qPCR demonstrated a dose-dependent suppression of IFNG mRNA expression in afatinib-treated T cells. Furthermore, afatinib impaired tumor rejection in an immunological memory mouse model that had been previously cured by anti–PD-L1 therapy, suggesting that afatinib may inhibit the function of effector memory T cells. Collectively, our findings highlight afatinib’s potential to impair T cell effector functions, indicating that strategic consideration is essential when combining epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKIs), including afatinib, with adoptive T cell therapies.