Xue et al. investigated mechanisms by which Th9 cells expressing tumor-specific TCRs or CARs eradicated advanced mouse tumors containing antigen-loss variants (ALVs). In contrast to Th1 or Th17 adoptive cell transfer, Th9 cells resulted in direct killing of Ag+ tumor cells and indirect killing of ALVs by promoting inflammatory monocyte chemotaxis with potent bystander ALV antitumor efficacy. Mechanistically, Th9 cells lack ATP-degrading CD39, producing high levels of intratumoral extracellular ATP, which resulted in stimulating monocyte infiltration and activation of innate dsRNA-sensing ERV-TLR3/MAVs pathways to produce IFNα/β and eliminate ALVs.
Contributed by Katherine Turner
ABSTRACT: Resistance can occur in patients receiving adoptive cell therapy (ACT) due to antigen-loss-variant (ALV) cancer cell outgrowth. Here we demonstrate that murine and human T helper (Th) 9 cells, but not Th1/Tc1 or Th17 cells, expressing tumor-specific T cell receptors (TCRs) or chimeric antigen receptors (CARs), 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 interferon (IFN) α/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 cluster of differentiation (CD) 39. Intratumor enrichment of eATP promotes the monocyte infiltration and stimulates their production of IFNα/β by inducing eATP-endogenous retrovirus-Toll-like receptor 3 (TLR3)/mitochondrial antiviral signaling (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.
Author Info: (1) Department of Microbiology & Immunology, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA. (2) Department of Microbiology & Immunology, Wake Forest School of Medici
Author Info: (1) Department of Microbiology & Immunology, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA. (2) Department of Microbiology & Immunology, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA. (3) Department of Microbiology & Immunology, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA. (4) Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA. (5) Department of Mathematics and Statistics, St. Cloud State University, St Cloud, MN 56301, USA. (6) Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. (7) Center for Translational Research in Hematologic Malignancies, Houston Methodist Cancer Center, Houston, TX 77030, USA. Electronic address: qyi@houstonmethodist.org. (8) Department of Microbiology & Immunology, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA. Electronic address: yolu@wakehealth.edu.
