T cell Tolerance as Function of Tumor Progression

Abstract

Event Abstract Back to Event T cell Tolerance as Function of Tumor Progression Meir Azulay1*, Yosi M. Gozlan1, Zoya Alteber1, Adi Shrbi Younger1, Esther Tzehoval1 and Lea Eisenbach1 1 Weizmann Institute of science, Immunology, Israel Determining how tumor immunity is regulated requires understanding the extent to which the anti-tumor immune response ‘‘functions’’ in vivo without therapeutic intervention. To better understand this question, we used traditional ex vivo analysis of tumor specific T cells. By transferring admixed splenocytes of melanoma-specific CD8+ T cells (pmel-1 and OT-I.GFP), we found that B16 tumor growth was sufficient to induce naïve pmel-1 and OT-I.GFP CD8+ T cell proliferation and acquisition of effector phenotype. However, pmel-1 T cells, were not capable of killing target cells, show decreased and low capacity to secrete IFNγ and TNF-α and were unable to mediate tumor regression. Within the tumor, pmel-1 T cells were proliferating extensively while their frequencies were decreasing rapidly. In contrast, OT-I.GFP T cells were able to mediate tumor regression and were capable of killing target cells in the tumor and in the periphery. While OT-I.GFP cells in the DLN were proliferating in low rates, cells isolated from the tumor show extensive proliferation capacity and long term interaction with B16 tumor cells. Suggesting that presentation of cognate peptide to pmel-1 T cells occurs during tumor growth already in the DLN which eventually leads to their elimination. These data indicates that lack of anti-tumor efficacy is not solely due to general immunosuppressive mechanisms in the tumor microenvironment but rather to active and specific peripheral tolerance mechanisms induced in the DLN. Recently, we have implicated the lymph node stroma in mediating CD8 T cell peripheral tolerance. We demonstrate that LN-resident lymphatic endothelial cells express peripheral tissue antigens and directly present an epitope derived from one of these, the melanocyte-specific protein PMEL17/gp100, to pmel-1 CD8 T cells, leading to their deletion. These results establish lymphatic endothelial cells, and potentially other LN-resident cells, as systemic mediators of peripheral immune tolerance. preventing a protective immune response.