IL-9 promotes the survival and function of human melanoma-infiltrating CD4(+) CD8(+) double-positive T cells

Eur J Immunol. 2016 Jul;46(7):1770-82. doi: 10.1002/eji.201546061. Epub 2016 May 6.


We previously demonstrated an accumulation of tumor-reactive CD4(+) CD8(+) double positive (DP) T cells within melanoma-infiltrating lymphocytes, supporting their role in the regulation of anti-tumor immune responses. Similarly to their CD8(+) counterparts, intra-tumor DP T cells are MHC class-I restricted but differed by a limited lytic activity against autologous melanoma cells. Based on these observations and to further characterize DP T cells, both populations were compared at the transcriptional level. Our results revealed the overexpression of the IL-9 receptor (IL-9R) by DP T cells and prompted us to investigate the impact of IL-9 on their biology. We show that IL-9 favors DP T-cell survival by protecting them from apoptosis and by promoting their proliferation. In addition, IL-9 enhances their ability to produce cytokines and increased their levels of granzyme B/perforin as well as degranulation capacity, leading to a strengthened cytotoxic activity against melanoma cells. Taken together, the IL-9R(high) DP T-cell population could be a new preferential target for IL-9, which could take part in their retention within the melanoma infiltrate while also favoring their anti-tumor activity. More generally, our results extend the pleiotropic effects of IL-9 to IL-9R-expressing intra-tumor T cells, which could further potentiate anti-tumor immune responses.

Keywords: CD4+CD8+ double-positive T lymphocyte; IL-9; IL-9R; Melanoma; TIL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / immunology
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Survival / immunology
  • Cells, Cultured
  • Cytokines / metabolism
  • Cytotoxicity, Immunologic / drug effects
  • Gene Expression
  • Humans
  • Interleukin-9 / immunology*
  • Interleukin-9 / pharmacology
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Lymphocytes, Tumor-Infiltrating / drug effects
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Lymphocytes, Tumor-Infiltrating / metabolism*
  • Melanoma / genetics
  • Melanoma / immunology*
  • Melanoma / metabolism*
  • Melanoma / pathology
  • Receptors, Interleukin-9 / genetics
  • Receptors, Interleukin-9 / metabolism
  • T-Lymphocyte Subsets / drug effects
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism*


  • Cytokines
  • Interleukin-9
  • Receptors, Interleukin-9