S. Patel1, T. Hoki1, T. Yamauchi1, K. A. Collins1, C. A. Eppolito1, A. J. Francois1, J. V. Welch1, J. A. DiTursi1, K. Odunsi1,2,3, F. Ito1,4,5 1Roswell Park Cancer Institute,Center For Immunotherapy,Buffalo, NY, USA 2Roswell Park Cancer Institute,Department Of Gynecologic Oncology,Buffalo, NY, USA 3Roswell Park Cancer Institute,Department Of Immunology,Buffalo, NY, USA 4State University Of New York At Buffalo,Department Of Surgery, University At Buffalo Jacobs School Of Medicine And Biomedical Sciences,Buffalo, NY, USA 5Roswell Park Cancer Institute,Department Of Surgical Oncology,Buffalo, NY, USA
Introduction:
Current approaches to adoptive cell therapy (ACT) with antigen-specific T cells are limited by the difficulty of obtaining sufficient numbers of T cells against targeted antigens with effective in vivo characteristics. Whereas interleukin (IL)-2 has been widely used for generation of antitumor T cells in vitro clinically, dose-dependent effects of IL-2 on differentiation of T cells are associated with decreased proliferative and self-renewal capacity in vivo. IL-7 and IL-15 are also common γ chain cytokines that play pivotal roles in homeostasis, proliferation, and maintenance of memory CD8+ T cells. Accumulating evidence largely from examining hematological malignancies indicates that the combined use of IL-7 and IL-15 (IL-7/15) can produce T cells that confer superior antitumor immunity in vivo. However, antitumor efficacy of IL-7/15-primed T cells in an orthotopic tumor model has not been rigorously evaluated.
Methods:
Pmel-1 T-cell receptor transgenic CD8+ T cells were activated with the cognate antigen gp100 expressed on B16 melanoma in IL-7/15 for 6 days. IL-2 was used for a control. Phenotype and function as well as metabolic profile of IL-2- and IL-7/15-primed T cells were evaluated. To determine in vivo antitumor efficacy, C57BL/6 mice bearing subcutaneous B16F10 melanoma were treated with adoptive transfer of IL-2- or IL-7/15-primed Pmel-1 T cells, followed by systemic administration of IL-2, and vaccination with gp100, anti-CD40 antibody, and toll-like receptor (TLR) agonist to augment antitumor efficacy of transferred T cells.
Results:
Cell expansion was significantly higher when T cells were activated in IL-7/15 at day 6 compared with ones in IL-2. IL-7/15-primed T cells consisted of a higher proportion of less-differentiated CD44+CD62L+ T cells, and secreted significantly more IL-2 against the target antigen compared to IL-2-primed T cells while both had comparable effector function such as specific lysis of targets and IFNγ production in vitro. Furthermore, IL-7/15-primed T cells had higher mitochondrial spare respiratory capacity than IL-2-primed T cells, suggesting that IL-7/15-primed T cells have capacity to produce more ATP in case of a sudden increase in energy demand. In line with this, adoptively-transferred IL-7/15-primed T cells expressed significantly higher Ki67 than IL-2-primed T cells in the tumor microenvironment (TME). Significantly delayed tumor growth and improved survival were observed in mice treated with IL-7/15-primed T cells compared to IL-2-primed T cells.
Conclusion:
Taken together, our studies suggest that IL-7/15 modulates the metabolic programming of T cells to promote more robust and efficient CD8+ T cells that can proliferate in the TME. In particular, IL-7/15-primed T cells have higher self-renewal and spare respiratory capacity with potent effector function that correspond to significantly improved survival in an orthotopic tumor model.