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Murine Th17 cells utilize IL-2 receptor gamma chain cytokines but are resistant to cytokine withdrawal-induced apoptosis

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Abstract

Adoptive cellular therapy (ACT) with the Th17 subset of CD4+ T cells can cure established melanoma in preclinical models and holds promise for treating human cancer. However, little is known about the growth factors necessary for optimal engraftment and anti-tumor activity of Th17 cells. Due to the central role of IL-2 receptor gamma chain (IL2Rγ-chain) cytokines (IL-2, IL-7, and IL-15) in the activity and persistence of many T cell subsets after adoptive transfer, we hypothesized that these cytokines are important for Th17 cells. We found that Th17 cells proliferated in response to IL-2, IL-7, and IL-15 in vitro. However, in contrast to many other T cell subsets, including conventionally activated CD8+ T cells, we found that Th17 cells were resistant to apoptosis in the absence of IL2Rγ-chain cytokines. To determine whether Th17 cells utilize IL2Rγ-chain cytokines in vivo, we tracked Th17 cell engraftment after adoptive transfer with or without cytokine depletion. Depletion of IL-7 and/or IL-2 decreased initial engraftment, while depletion of IL-15 did not. Supplementation of IL-2 increased initial Th17 engraftment. To assess the clinical relevance of these findings, we treated melanoma-bearing mice with Th17 cell adoptive transfer and concurrent cytokine depletion or supplementation. We found that simultaneous depletion of IL-2 and IL-7 decreased therapeutic efficacy, depletion of IL-15 had no effect, and IL-2 supplementation increased therapeutic efficacy. Our results show that Th17 cells are responsive to IL2Rγ-chain cytokines, and provide insight into the application of these cytokines for Th17-based therapeutic strategies.

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Abbreviations

Akt:

Protein kinase B

B6:

C57BL/6

Bcl-2:

B-cell lymphoma 2

Bcl-xl:

B-cell lymphoma extra-large

BrdU:

5-bromo-2′-deoxyuridine

c-FLIP:

c-Fas-associated death domain-like interleukin-1-converting enzyme inhibitory protein

FoxO1:

Forkhead box protein O1

γδ T cells:

Gamma delta T cells

hgp100:

Human melanoma antigen gp100

IL2Rγ-chain cytokines:

Cytokines which signal through the common gamma chain (CD132) – here:IL-2, IL-7, and IL-15

Ki67:

Ki67 protein (proliferation marker)

Klf2:

Kruppel-like factor 2

MEK:

Mitogen activated protein kinase (MAPK) kinase

mTOR:

Mammalian target of rapamycin

NK:

Natural killer

NKT:

Natural killer T

PMA:

Phorbol 12-myristate 13-acetate

RAG-1:

Recombination activating gene 1

S6:

Ribosomal protein S6

Tc1:

T cytotoxic 1 subset

Tc17:

T cytotoxic 17 subset

Th17:

T helper 17 subset

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Acknowledgements

We thank Casey White for assistance with tumor measurement. Support for this project was provided by the following grants and fellowships from the National Institutes of Health and National Cancer Institute: F30CA200272 (Jacob Bowers), T32GM008716 (Daniel Neitzke and Jacob Bowers), 5P01CA186866 (Zihai Li), 5R01CA188419 (Zihai Li), and 5R01CA175061 (Chrystal Paulos). We are also grateful to the Melanoma Research Alliance for grant funding (Mark Rubinstein). This work was also supported in part by the Biostatistics and the Cell Evaluation & Therapy Shared Resource, Hollings Cancer Center, Medical University of South Carolina (P30CA138313). We are grateful to Amgen for kindly providing anti-IL-15 mAb (clone M96).

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Authors and Affiliations

  1. Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA

    Daniel J. Neitzke, Kristina Andrijauskaite & David J. Cole

  2. Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA

    Jacob S. Bowers, Zihai Li & Chrystal M. Paulos

  3. Department of Public Health Sciences, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA

    Nathaniel S. O’Connell & Elizabeth Garrett-Mayer

  4. Department of Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA

    John Wrangle

  5. Departments of Surgery, and Microbiology and Immunology, Medical University of South Carolina, 86 Jonathan Lucas Street, Hollings Cancer Center Room 506, Charleston, SC, 29425, USA

    Mark P. Rubinstein

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  1. Daniel J. Neitzke
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Neitzke, D.J., Bowers, J.S., Andrijauskaite, K. et al. Murine Th17 cells utilize IL-2 receptor gamma chain cytokines but are resistant to cytokine withdrawal-induced apoptosis. Cancer Immunol Immunother 66, 737–751 (2017). https://doi.org/10.1007/s00262-017-1965-3

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