Th9 Cells Represent a Unique Subset of CD4+ T Cells Endowed with the Ability to Eradicate Advanced Tumors

Cancer Cell. 2018 Jun 11;33(6):1048-1060.e7. doi: 10.1016/j.ccell.2018.05.004.

Abstract

The antitumor effector T helper 1 (Th1) and Th17 cells represent two T cell paradigms: short-lived cytolytic Th1 cells and "stem cell-like" memory Th17 cells. We report that Th9 cells represent a third paradigm-they are less-exhausted, fully cytolytic, and hyperproliferative. Only tumor-specific Th9 cells completely eradicated advanced tumors, maintained a mature effector cell signature with cytolytic activity as strong as Th1 cells, and persisted as long as Th17 cells in vivo. Th9 cells displayed a unique Pu.1-Traf6-NF-κB activation-driven hyperproliferative feature, suggesting a persistence mechanism rather than an antiapoptotic strategy. Th9 antitumor efficacy depended on interleukin-9 and upregulated expression of Eomes and Traf6. Thus, tumor-specific Th9 cells are a more effective CD4+ T cell subset for adoptive cancer therapy.

Keywords: T cell paradigm; adoptive cell therapy; eradication of large advanced tumor; tumor-specific Th9 cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Line, Tumor
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / immunology
  • Immunotherapy, Adoptive / methods
  • Interleukin-9 / genetics
  • Interleukin-9 / immunology*
  • Interleukin-9 / metabolism
  • Melanoma, Experimental / genetics
  • Melanoma, Experimental / immunology*
  • Melanoma, Experimental / therapy
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / genetics
  • NF-kappa B / immunology
  • NF-kappa B / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / immunology
  • Proto-Oncogene Proteins / metabolism
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocytes, Helper-Inducer / immunology*
  • T-Lymphocytes, Helper-Inducer / metabolism
  • TNF Receptor-Associated Factor 6 / genetics
  • TNF Receptor-Associated Factor 6 / immunology
  • TNF Receptor-Associated Factor 6 / metabolism
  • Trans-Activators / genetics
  • Trans-Activators / immunology
  • Trans-Activators / metabolism

Substances

  • IL9 protein, human
  • Interleukin-9
  • NF-kappa B
  • Proto-Oncogene Proteins
  • TNF Receptor-Associated Factor 6
  • Trans-Activators
  • proto-oncogene protein Spi-1