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 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.

• Authors: Ningbo Zheng, Jing Fang, Gang Xue, Ziyu Wang, Xiaoyin Li, Mengshi Zhou, Guangxu Jin, Masmudur M Rahman, Grant McFadden, Yong Lu
• Journal: Cancer cell (Cancer Cell) Vol. 40 Issue 9 Pg. 973-985.e7 (09 12 2022) ISSN: 1878-3686 [Electronic] United States
• PMID: 36027915 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Inc. All rights reserved.

Chemical References

• Receptors, Antigen, T-Cell
• Receptors, Chimeric Antigen

Topics

• Humans
• Immunotherapy, Adoptive
• Myxoma virus (physiology)
• Neoplasms
• Receptors, Antigen, T-Cell
• Receptors, Chimeric Antigen (genetics)
• T-Lymphocytes