Dendritic Cells in Irradiated Mice Trigger the Functional Plasticity and Antitumor Activity of Adoptively Transferred Tc17 Cells via IL12 Signaling

Purpose: The adoptive cell transfer (ACT) of CD8(+) T cells is a promising treatment for advanced malignancies. Lymphodepletion before ACT enhances IFN gamma(+)CD8(+) T cell (Tc0)-mediated tumor regression. Yet, how lymphodepletion regulates the function and antitumor activity of IL17A(+)CD8(+) T cells (Tc17) is unknown. Experimental Design: To address this question, pmel-1 CD8(+) T cells were polarized to secrete either IL17A or IFN gamma. These subsets were then infused into mice with B16F10 melanoma that were lymphoreplete [no total body irradiation (TBI)], or lymphodepleted with nonmyeloablative (5 Gy) or myeloablative (9 Gy with hematopoietic stem cell transplantation) TBI. The activation of innate immune cells and function of donor T-cell subsets were monitored in recipient mice. Results: Tc17 cells regress melanoma in myeloablated mice to a greater extent than in lymphoreplete or nonmyeloablated mice. TBI induced functional plasticity in Tc17 cells, causing conversion from IL17A to IFN gamma producers. Additional investigation revealed that Tc17 plasticity and antitumor activity were mediated by IL12 secreted by irradiated host dendritic cells (DC). Neutralization of endogenous IL12 reduced the antitumor activity of Tc17 cells in myeloablated mice, whereas ex vivo priming with IL12 enhanced their capacity to regress melanoma in nonmyeloablated animals. This, coupled with exogenous administration of low-dose IL12, obviated the need for host preconditioning, creating curative responses in nonirradiated mice. Conclusions: Our findings indicate that TBI-induced IL12 augments Tc17 cell-mediated tumor immunity and underline the substantial implications of in vitro preparation of antitumor Tc17 cells with IL12 in the design of T-cell immunotherapies. (C)2015 AACR.