Abstract
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 developed advanced multimodal reflectance confocal/two photon fluorescence intra-vital imaging techniques to use in combination with traditional ex vivo analysis of tumor specific T cells. By transferring small numbers of melanoma-specific CD8+ T cells (Pmel-1), in an attempt to mimic physiologic conditions, we found that B16 tumor growth alone was sufficient to induce naive Pmel-1 T cell proliferation and acquisition of effector phenotype. Tumor -primed Pmel-1 T cells, are capable of killing target cells in the periphery and secrete IFNγ, but are unable to mediate tumor regression. Within the tumor, Pmel-1 T cells have highly confined mobility, displaying long term interactions with tumor cells. In contrast, adoptively transferred non tumor-specific OT-I T cells show neither confined mobility, nor long term interaction with B16 tumor cells, suggesting that intra-tumor recognition of cognate self antigen by Pmel-1 T cells occurs during tumor growth. Together, these data indicate that lack of anti-tumor efficacy is not solely due to ignorance of self antigen in the tumor microenvironment but rather to active immunosuppressive influences preventing a protective immune response.
Highlights
It is known that the immune system can generate responses to antigens expressed by cancer cells [1]
A more detailed analysis of the leukocyte/ myeloid infiltrate was accomplished after density gradient centrifugation of the tumors (Fig. 1B). ,40% of the CD4+ cells present in the tumor were Foxp3+ Tregs, demonstrating a selective recruitment of inhibitory cells to the tumor as a portion of total leukocytes compared to the tumor-draining lymph node (TDLN)
Through the combination of ex-vivo and in-vivo analysis, we have shown that the immune system is capable of generating an anti-tumor response which is able to engage in intra-tumor recognition of cognate self tumor antigen
Summary
It is known that the immune system can generate responses to antigens expressed by cancer cells [1]. Barriers remain at the level of the tumor, and possibly in the secondary lymphoid organs, which prevent effective cancer immunity [2,3]. A growing body of evidence suggests active inhibition of T cell effector functions by tumor cells and/or cells of the tumor stroma [5,6,7] Passive processes, such as immune ignorance or deletion of highly reactive ‘‘self’’ T cell clones during central tolerance induction may prevent tumor eradication [8]. The processes that avert autoimmunity may prevent the generation of effective anti-tumor immunity [9]. While these various mechanisms have different mediators and temporal separations, they may not be mutually exclusive. It is possible that multiple processes cooperate to prevent effective tumor immunity
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