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A cytokine cocktail directly modulates the phenotype of DC-enriched anti-tumor T cells to convey potent anti-tumor activities in a murine model

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Abstract

Adoptive cell transfer (ACT) using ex vivo-expanded anti-tumor T cells such as tumor-infiltrated lymphocytes or genetically engineered T cells potently eradicates established tumors. However, these two approaches possess obvious limitations. Therefore, we established a novel methodology using total tumor RNA (ttRNA) to prime dendritic cells (DC) as a platform for the ex vivo generation of anti-tumor T cells. We evaluated the antigen-specific expansion and recognition of T cells generated by the ttRNA–DC–T platform, and directly modulated the differentiation status of these ex vivo-expanded T cells with a cytokine cocktail. Furthermore, we evaluated the persistence and in vivo anti-tumor efficacy of these T cells through murine xenograft and syngeneic tumor models. During ex vivo culture, IL-2 preferentially expanded CD4 subset, while IL-7 enabled homeostatic proliferation from the original precursors. T cells tended to lose CD62L during ex vivo culture using IL-2; however, IL-12 could maintain high levels of CD62L by increasing expression on effector T cells (Tem). In addition, we validated that OVA RNA–DC only selectively expanded T cells in an antigen-specific manner. A cytokine cocktail excluding the use of IL-2 greatly increased CD62Lhigh T cells which specifically recognized tumor cells, engrafted better in a xenograft model and exhibited superior anti-tumor activities in a syngeneic intracranial model. ACT using the ex vivo ttRNA–DC–T platform in conjunction with a cytokine cocktail generated potent CD62Lhigh anti-tumor T cells and imposes a novel T cell-based therapeutic with the potential to treat brain tumors and other cancers.

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Acknowledgments

We thank Dr. Kendra Congdon for proofreading of the manuscript. This study was supported by NIH grants (5P50-CA108786, 3R21CA132891-02S1, 5R01-CA135272-05, 5R21NS067975-02, 5R21NS067980-02, 5R21NS068057-02, 3R01CA135272-02S1, R25-NS065731, 5P50-NS020023-29, 1P01-CA154291-01A1), and by Accelerate Brain Cancer Cure, National Brain Tumor Society, American Brain Tumor Association, Pediatric Brain Tumor Foundation of the United States, Goldhirsh Foundation, Brain Tumor Society, Ivy Foundation DTRI, Duke University Biomarker Factory Duke Cancer Institute, Duke Chandran.

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The authors declare that they have no conflict of interest.

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  1. Shicheng Yang

    Present address: YZY Personalized Medicine Research Institute, Huazhong University of Science and Technology, Wuhan YZY Biopharma Company, 666 Gaoxin Road, Wuhan, 430075, China

Authors and Affiliations

  1. Division of Neurosurgery, Department of Surgery, Brain Tumor Immunotherapy Program, Duke University Medical Center, 303 Research Drive, 220 Sands Building, DUMC 3050, Durham, NC, 27710, USA

    Shicheng Yang, Gary E. Archer, Catherine E. Flores, Duane A. Mitchell & John H. Sampson

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Yang, S., Archer, G.E., Flores, C.E. et al. A cytokine cocktail directly modulates the phenotype of DC-enriched anti-tumor T cells to convey potent anti-tumor activities in a murine model. Cancer Immunol Immunother 62, 1649–1662 (2013). https://doi.org/10.1007/s00262-013-1464-0

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