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Interleukin-12 enhances the function and anti-tumor activity in murine and human CD8+ T cells

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Abstract

Mouse CD8+ T cells conditioned with interleukin (IL)-12 ex vivo mediate the potent regression of established melanoma when transferred into lymphodepleted mice. However, the quantitative and qualitative changes induced by IL-12 in the responding mouse CD8+ T cells have not been well defined. Moreover, the mechanisms by which IL-12-conditioning impacts human CD8+ T cells, and how such cells might be expanded prior to infusion into patients is not known. We found that ex vivo IL-12-conditioning of mouse CD8+ T cells led to a tenfold–100-fold increase in persistence and anti-tumor efficacy upon adoptive transfer into lymphodepleted mice. The enhancing effect of IL-12 was associated with maintenance of functional avidity. Importantly, in the context of ongoing ACT clinical trials, human CD8+ T cells genetically modified with a tyrosinase-specific T cell receptor (TCR) exhibited significantly enhanced functional activity when conditioned with IL-12 as indicated by heightened granzyme B expression and elevated peptide-specific CD107a degranulation. This effect was sustainable despite the 20 days of in vitro cellular expansion required to expand cells over 1,000-fold allowing adequate cell numbers for administration to cancer patients. Overall, these findings support the efficacy and feasibility of ex vivo IL-12-conditioning of TCR-modified human CD8+ T cells for adoptive transfer and cancer therapy.

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Abbreviations

ACT:

Adoptive cell therapy

CAR:

Chimeric antigen receptor

CTX:

Cyclophosphamide

IL-12:

Interleukin-12

REP:

Rapid expansion protocol

Tc0:

CD8+ T cells not polarized

Tc1:

CD8+ T cells polarized with IL-12

TCR:

T cell receptor

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Acknowledgments

We thank Daniel Neitzke for critical review of this manuscript. Grant funding for this project was provided by the following grants from the National Institutes of Health and the National Cancer Institute: P01CA54778-01, R01CA138930, R01CA133503, and R01CA175061. This work was also supported in part by pilot research funding and also the Cell Evaluation and Therapy Shared Resource, Hollings Cancer Center, Medical University of South Carolina (P30CA138313).

Conflict of interest

The authors have no conflicts of interest to declare.

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Authors and Affiliations

  1. Department of Surgery, Medical University of South Carolina, 86 Jonathan Lucas Street, HO506, Charleston, SC, 29425, USA

    Mark P. Rubinstein, Ee Wern Su, Samantha Suriano, Colleen A. Cloud, Kristina Andrijauskaite, Pravin Kesarwani, Kristina M. Schwartz, Katelyn M. Williams, C. Bryce Johnson, Mingli Li, Chrystal M. Paulos, Shikhar Mehrotra & David J. Cole

  2. Loyola University Chicago, Maywood, IL, 60153, USA

    Gina M. Scurti

  3. Immunology and Biotechnology Unit, Zoology Department, Faculty of Science, and Center of Excellence in Cancer Research, Tanta University, Tanta, Egypt

    Mohamed L. Salem

  4. Department of Public Health, Medical University of South Carolina, Charleston, SC, 29425, USA

    Elizabeth Garrett-Mayer

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  1. Mark P. Rubinstein
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Correspondence to Mark P. Rubinstein.

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Rubinstein, M.P., Su, E.W., Suriano, S. et al. Interleukin-12 enhances the function and anti-tumor activity in murine and human CD8+ T cells. Cancer Immunol Immunother 64, 539–549 (2015). https://doi.org/10.1007/s00262-015-1655-y

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