Afatinib exerts an inhibitory effect on T cell-mediated cytotoxicity

Area of Science:

• Immunology
• Cancer Biology
• Pharmacology

Background:

• Adoptive T cell therapy is effective for hematologic cancers and being explored for solid tumors.
• Combining T cell therapy with conventional treatments may enhance efficacy.
• Inhibitor screening evaluated effects on T cell-mediated cytotoxicity against cancer cells.

Purpose of the Study:

• To identify inhibitors affecting T cell-mediated cytotoxicity.
• To evaluate afatinib's impact on T cell function and anti-cancer activity.
• To assess implications for combining EGFR-TKIs with adoptive T cell therapy.

Main Methods:

• In vitro inhibitor screening.
• RNA-sequencing (RNA-seq) to analyze T cell receptor (TCR) pathway.
• Quantitative real-time PCR (RT-qPCR) to measure IFNG mRNA expression.
• Immunological memory mouse model to assess tumor rejection.

Main Results:

• Afatinib was identified as an immunosuppressive agent.
• Afatinib reduced interferon-γ (IFN-γ) secretion and T cell activation, independent of proliferation.
• RNA-seq showed afatinib downregulated the TCR pathway signature.
• Afatinib suppressed IFNG mRNA expression in a dose-dependent manner.
• Afatinib impaired tumor rejection in a mouse model, suggesting inhibition of effector memory T cells.

Conclusions:

• Afatinib impairs T cell effector functions, including IFN-γ secretion and cytotoxic activity.
• Combining afatinib (an EGFR-TKI) with adoptive T cell therapy requires careful strategic consideration.
• Afatinib may negatively impact the efficacy of T cell-based cancer immunotherapies.