Abstract 5504: Adoptive cell therapy with tumor-specific Th9 cells induces viral mimicry to restrain acquired resistance from antigen-loss-variant tumor cells

Abstract

Abstract Adoptive cell therapy (ACT) with tumor-specific T cells expressing T-cell-receptors (TCR) or chimeric antigen receptors (CAR) has not mediated sustained responses in solid tumors. Several factors limit the efficacy of ACT in solid tumors and lead to primary resistance and acquired resistance (refers to recurrence after the initial response). These include but not limited to the insufficient proliferation of T cells, the low capacity of T cells to penetrate stroma-rich solid tumors, and heterogeneity of antigen expression in solid tumors, which allows the escape of T cell attack by tumor cells when becoming antigen-loss-variant cancer cell (ALV). Hence, it is urgent to develop novel ACT strategies to eradicate solid tumors and prevent acquired resistance. We have previously reported (Yong Lu, Cancer Cell, 2018) that tumor-specific IL-9-producing CD4+ Th9 cells represent a novel T cell paradigm for ACT - they are less exhausted, fully cytolytic, and hyperproliferative. This hyperproliferation of Th9 cells is driven by a unique Th9 master transcriptional factor Pu.1 mediated Pu.1-Traf6-NFκB signaling to ensure Th9 cells persist as long as “stem cell-like” T cells, which is not presented in other known CD4+ T cells subsets. In our most recent study, we demonstrate that murine and human Th9 cells, but not Th1/Tc1 or Th17 cells, expressing tumor-specific T-cell-receptors (TCR) or chimeric antigen receptors (CAR), eradicate advanced tumors that contain ALVs. This unprecedented antitumor capacity of Th9 cells is attributed to both enhanced direct tumor cell killing and bystander antitumor effects promoted by intratumor release of IFNα/β. Mechanistically, tumor-specific Th9 cells increase the intratumor accumulation of extracellular ATP (eATP, released from dying tumor cells), because of a unique feature of Th9 cells that lack the expression of ATP degrading ectoenzyme CD39. Intratumor enrichment of eATP promotes the monocyte infiltration and stimulates their production of IFNα/β by inducing eATP-endogenous retrovirus-TLR3/MAVS pathway activation. These results identify tumor-specific Th9 cells as a unique T cell subset endowed with the unprecedented capacity to eliminate ALVs for curative responses. Citation Format: Yong Lu. Adoptive cell therapy with tumor-specific Th9 cells induces viral mimicry to restrain acquired resistance from antigen-loss-variant tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5504.