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Priming of naive CD8+ T cells in the presence of IL-12 selectively enhances the survival of CD8+CD62Lhi cells and results in superior anti-tumor activity in a tolerogenic murine model

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Abstract

During the antigen-dependant activation process several subsets CD8+ T cells appear with different phenotypic and functional characteristics. Recent studies indicate that the state of T cell differentiation radically affects their ability to effectively respond to tumor challenge, with early effector CD8+ T (CD62Lhigh) cells having better anti-tumor activity. Thus strategies aimed at optimizing the generation of such subpopulations could significantly enhance the effectiveness of adoptive cell therapy (ACT) for cancer. In this study, we show that priming of naïve CD8+ T cells in the presence of IL-12 selectively rescued early CD8+ CD62Lhi from activation induced cell death and resulted in the increased accumulation of this subset of CD8+ T cells. Furthermore, we demonstrated that IL-12 directly modulated the expression of CD62L on activated CD8+ T cells. When used for ACT, naïve CD8+ T cells primed in vitro in the presence of IL-12 showed superior anti-tumor activity toward B16 melanoma. Importantly, using the Pmel-1 model, priming pmel-1 cells in vitro with IL-12 reduced the state of functional tolerance associated with the non-mutated “self” tumor antigen gp100, as demonstrated by significant tumor responses in the absence of vaccination. Together, our results suggest that in vitro conditioning of naïve CD8+ T cells with IL-12 prior to ACT could significantly enhance their anti-tumor activity.

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Acknowledgments

This work was supported by the National Institutes of Health Grant 1 R01 CA94856-01. We thank Dr. Yian Chen and Elizabeth Little for technical assistance.

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Authors and Affiliations

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

    C. Marcela Díaz-Montero, Amir Al Khami, David J. Cole & Mohamed L. Salem

  2. Department of Zoology, Tanta University, Tanta, Egypt

    Sabry El Naggar & Randa El Naggar

  3. Departments of Medicine, Medical University of South Carolina, Charleston, SC, USA

    Alberto J. Montero

Authors
  1. C. Marcela Díaz-Montero
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  2. Sabry El Naggar
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  3. Amir Al Khami
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Correspondence to Mohamed L. Salem.

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Díaz-Montero, C.M., El Naggar, S., Al Khami, A. et al. Priming of naive CD8+ T cells in the presence of IL-12 selectively enhances the survival of CD8+CD62Lhi cells and results in superior anti-tumor activity in a tolerogenic murine model. Cancer Immunol Immunother 57, 563–572 (2008). https://doi.org/10.1007/s00262-007-0394-0

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  • DOI: https://doi.org/10.1007/s00262-007-0394-0

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