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 Chapoval, Ronald B. Gartenhaus, Scott E. Strome, Brian R. Gastman

Research output: Contribution to journalArticle

13 Citations (Scopus)

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
Externally publishedYes

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Interleukin-7
Immunotherapy
T-Lymphocytes
Neoplasms
Aptitude
1-Phosphatidylinositol 4-Kinase
Glycogen Synthase Kinase 3
Coculture Techniques
Small Interfering RNA
Interleukin-2
Research Design
Phosphorylation
Cytokines
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Interleukin-7 inhibits tumor-induced CD27 -CD28 - suppressor T cells : Implications for cancer immunotherapy. / Zhang, Yue; Pfannenstiel, Lukas W.; Bolesta, Elzbieta; Montes, Carolina L.; Zhang, Xiaoyu; Chapoval, Andrei; Gartenhaus, Ronald B.; Strome, Scott E.; Gastman, Brian R.

In: Clinical Cancer Research, Vol. 17, No. 15, 01.08.2011, p. 4975-4986.

Research output: Contribution to journalArticle

Zhang, Y, Pfannenstiel, LW, Bolesta, E, Montes, CL, Zhang, X, Chapoval, A, Gartenhaus, RB, Strome, SE & Gastman, BR 2011, 'Interleukin-7 inhibits tumor-induced CD27 -CD28 - suppressor T cells: Implications for cancer immunotherapy', Clinical Cancer Research, vol. 17, no. 15, pp. 4975-4986. https://doi.org/10.1158/1078-0432.CCR-10-3328
Zhang, Yue ; Pfannenstiel, Lukas W. ; Bolesta, Elzbieta ; Montes, Carolina L. ; Zhang, Xiaoyu ; Chapoval, Andrei ; Gartenhaus, Ronald B. ; Strome, Scott E. ; Gastman, Brian R. / Interleukin-7 inhibits tumor-induced CD27 -CD28 - suppressor T cells : Implications for cancer immunotherapy. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 15. pp. 4975-4986.
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AU - Bolesta, Elzbieta

AU - Montes, Carolina L.

AU - Zhang, Xiaoyu

AU - Chapoval, Andrei

AU - Gartenhaus, Ronald B.

AU - Strome, Scott E.

AU - Gastman, Brian R.

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N2 - 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.

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