Adoptive cell therapy with tumor-specific Th9 cells induces viral mimicry to eliminate antigen-loss-variant tumor cells

Gang Xue, Ningbo Zheng, Jing Fang, Guangxu Jin, Xiaoyin Li, Gianpietro Dotti, Qing Yi, Yong Lu

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1610-1622.e9
JournalCancer Cell
Volume39
Issue number12
DOIs
StatePublished - Dec 13 2021

Keywords

  • Adoptive cell therapy
  • Th9
  • type I IFN
  • antigen-loss variant cancer cells
  • Immunotherapy, Adoptive/methods
  • Cell- and Tissue-Based Therapy/methods
  • Humans
  • Interleukin-9/genetics
  • Cell Line, Tumor
  • Cell Differentiation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Cell Biology

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