Interleukin-7 inhibits tumor-induced CD27 -CD28 - suppressor T cells: Implications for cancer immunotherapy

Yue Zhang, Lukas W. Pfannenstiel, Elzbieta Bolesta, Carolina L. Montes, Xiaoyu Zhang, Andrei I. Chapoval, Ronald B. Gartenhaus, Scott E. Strome, Brian R. Gastman

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Purpose: We have previously reported that many types of tumors can induce changes in human T cells that lead to the acquisition of suppressive function and phenotypic alterations resembling those found in senescent T cells. In the present study, we find a role for interleukin 7 (IL-7) in protecting T cells from these changes and further define involved signaling pathways. Experimental Design: We evaluated the ability of IL-7 treatment to prevent the gain of suppressive function and phenotypic alterations in human T cells after a short coculture with tumor cells in vitro. We then used inhibitors of components of the phosphoinositide 3-kinase (PI3K)/AKT pathway and short interfering RNA knockdown of Mcl-1 and Bim to evaluate the role of these signaling pathways in IL-7 protection. Results: We found that IL-7 inhibits CD27/CD28 loss and maintains proliferative capacity, IL-2 production, and reduced suppressive function. The protective ability of IL-7 depended on activation of the PI3K/AKT pathway, which inhibited activation of glycogen synthase kinase 3β, which, in turn, prevented the phosphorylation and loss of Mcl-1. We further showed a key role for Mcl-1 in that its knockdown or inhibition abrogated the effects of IL-7. In addition, knockdown of the Mcl-1 binding partner and proapoptotic protein Bim protected T cells from these dysfunctional alterations. Conclusion: These observations confirm the role for Bcl-2 family members in cytokine signaling and suggest that IL-7 treatment in combination with other immunotherapies could lead to new clinical strategies to maintain normal T-cell function and reduce tumor-induced generation of dysfunctional and suppressor T cells.

Original languageEnglish (US)
Pages (from-to)4975-4986
Number of pages12
JournalClinical Cancer Research
Volume17
Issue number15
DOIs
StatePublished - Aug 1 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Zhang, Y., Pfannenstiel, L. W., Bolesta, E., Montes, C. L., Zhang, X., Chapoval, A. I., Gartenhaus, R. B., Strome, S. E., & Gastman, B. R. (2011). Interleukin-7 inhibits tumor-induced CD27 -CD28 - suppressor T cells: Implications for cancer immunotherapy. Clinical Cancer Research, 17(15), 4975-4986. https://doi.org/10.1158/1078-0432.CCR-10-3328