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

Ningbo Zheng, Jing Fang, Gang Xue, Ziyu Wang, Xiaoyin Li, Mengshi Zhou, Guangxu Jin, Masmudur M. Rahman, Grant McFadden, Yong Lu

Research output: Contribution to journalArticlepeer-review

Abstract

Summary Cytotoxicity of tumor-specific T cells 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 T cell receptor (TCR), which systemically deliver MYXV into solid tumors to overcome primary resistance. In addition to T cell-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, T cell-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 T cells and MYXV to bolster solid tumor cell autosis that reinforces tumor clearance.
Original languageEnglish (US)
Pages (from-to)973
JournalCancer Cell
Volume40
Issue number9
DOIs
StatePublished - Sep 12 2022

Keywords

  • CAR-T cells
  • myxoma virus
  • autosis
  • acquired resistance

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