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.

由于抗原丢失变异（ALV）癌细胞生长，接受过继细胞疗法（ACT）的患者可能会出现耐药性。在这里，我们证明表达肿瘤特异性 T 细胞受体 (TCR) 或嵌合抗原受体 (CAR) 的小鼠和人类辅助性 T (Th) 9 细胞（而非 Th1/Tc1 或 Th17 细胞）能够根除含有 ALV 的晚期肿瘤。Th9 细胞这种前所未有的抗肿瘤能力归因于增强的直接肿瘤细胞杀伤作用和肿瘤内释放的干扰素 (IFN) α/β 促进的旁观者抗肿瘤作用。从机制上讲，肿瘤特异性 Th9 细胞增加了细胞外 ATP（eATP；从垂死的肿瘤细胞释放）的肿瘤内积累，因为 Th9 细胞缺乏 ATP 降解胞外酶分化簇 (CD) 39 表达的独特特征。 肿瘤内富集eATP 通过诱导 eATP-内源性逆转录病毒-Toll 样受体 3 (TLR3)/线粒体抗病毒信号 (MAVS) 通路激活，促进单核细胞浸润并刺激其产生 IFNα/β。这些结果表明肿瘤特异性 Th9 细胞是一种独特的 T 细胞亚群，具有前所未有的消除 ALV 以获得治疗反应的能力。