Induction of tumor cell autosis by myxoma virus-infected CAR-T and TCR-T cells to overcome primary and acquired resistance.

Abstract

Cytotoxicity of tumor-specific Tcells requires tumor cell-to-T cell contact-dependent induction of classic tumor cell apoptosis and pyroptosis. However, this may not trigger sufficient primary responses of solid tumors to adoptive cell therapy or prevent tumor antigen escape-mediated acquired resistance. Here we test myxoma virus (MYXV)-infected tumor-specific T (TMYXV) cells expressing chimeric antigen receptor (CAR) or Tcell receptor (TCR), which systemically deliver MYXV into solid tumors to overcome primary resistance. In addition to Tcell-induced apoptosis and pyroptosis, tumor eradication by CAR/TCR-TMYXV cells is also attributed to tumor cell autosis induction, a special type of cell death. Mechanistically, Tcell-derived interferon γ (IFNγ)-protein kinase B (AKT) signaling synergizes with MYXV-induced M-T5-SKP-1-VPS34 signaling to trigger robust tumor cell autosis. CAR/TCR-TMYXV-elicited autosis functions as a type of potent bystander killing to restrain antigen escape. We uncover an unexpected synergy between Tcells and MYXV to bolster solid tumor cell autosis that reinforces tumor clearance.