title: A cytokine cocktail directly modulates the phenotype of DC-enriched anti-tumor T cells to convey potent anti-tumor activities in a murine model.
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.
authors: 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.
authors: Shicheng
authors: S
authors: Yang
authors: Gary E
authors: GE
authors: Archer
authors: Catherine E
authors: CE
authors: Flores
authors: Duane A
authors: DA
authors: Mitchell
authors: John H
authors: JH
authors: Sampson
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000276:immunology* / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D016130:Immunophenotyping; D016219:Immunotherapy, Adoptive / Q000379:methods; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D019041:L-Selectin / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D012334:RNA, Neoplasm / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D023041:Xenograft Model Antitumor Assays
chemical_list: D016207:Cytokines; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D012334:RNA, Neoplasm; D019041:L-Selectin
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