Characterization of naïve T Cell Infiltration into Tumors and Their in Situ Activation and Effector Differentiation

Thompson, Elizabeth Dell, Department of Microbiology, University of Virginia
Engelhard, Victor, Department of Microbiology, University of Virginia
Bullock, Timothy, Department of Pathology, University of Virginia
Tung, Kenneth, Department of Pathology, University of Virginia
Bouton, Amy, Department of Microbiology, University of Virginia
Lorenz, Ulrike, Department of Microbiology, University of Virginia

Studies of T cell responses to tumors have focused on the draining lymph node (LN) as the site of activation. We examined the tumor mass as a potential site of activation following adoptive transfer of naïve tumor-specific CD8 T cells. Activated CD8 T cells were present in tumors within 24 h of adoptive transfer and proliferation of these cells was also evident 4-5 d later in mice treated with FTY720 to prevent infiltration of cells activated in LN. To confirm that activation of these T cells occurred in the tumor and not the tumor draining LN, we utilized mice lacking LN. Activated and proliferating tumor infiltrating lymphocytes were evident in these mice 24 h and 4 d after naïve cell transfer. T cells activated within tumors acquired effector function that was evident both ex vivo and in vivo. These results extend to tumors in different anatomic locations, different tumor types, and different tumor specific T cell receptors (TCR). Both cross-presenting antigen presenting cells (APC) within the tumor or tumor cells directly presenting antigen activated these functional CD8 effectors. We also investigated the mechanism by which naïve T cells infiltrate tumor masses in different anatomic locations. Expression of CD62L,  4 integrin, and CD11a were all required for naïve T cell infiltration into subcutaneous (SC) tumors, while only CD62L and CD11a were required for infiltration of intraperitoneal (IP) tumors. Expression of CCR7 was required for optimal naïve T cell infiltration of tumors in both locations. Studies in immunodeficient mice suggested that different populations of endogenous lymphocytes support naïve T cell infiltration in each tumor location: natural killer (NK) cells in subcutaneous tumors, and CD8 T cells in intraperitoneal tumors. In addition, lymphocytes were differentially activated in each tumor location, with lymphocytes in SC tumors producing more interferon (IFN)-than in ii intraperitoneal tumors, as well as tumor necrosis factor (TNF)-, which was not produced in IP tumors. Paradoxically, infiltration of naïve T cells into IP tumors was dependent on endogenous IFN-, while infiltration into SC tumors was not, indicating that the increased production other inflammatory mediators in SC tumors can compensate for that lack of endogenous IFN-. We conclude that tumors support the infiltration, activation, and effector differentiation of naïve CD8 T cells, despite the presence of immunosuppressive mechanisms. Therefore, targeting of T cell activation to tumors may present a tool in the development of cancer immunotherapy.

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PHD (Doctor of Philosophy)
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