COBRE: DMS: MECHANISMS OF CONCOMITANT TUMOR IMMUNITY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Concomitant tumor immunity is defined as the rejection of a secondary tumor in a host bearing a progressive primary tumor. We have recently shown that concomitant immunity exists for poorly-immunogenic melanoma if CD4+ CD25+ regulatory T cells are absent during tumor progression. This protective anti-tumor immunity is mediated by CD8+ T cells, and can be induced experimentally by total depletion of CD4+ T cells. Concomitant immunity for poorly-immunogenic melanoma is also characterized by the breaking of immunological tolerance to tumor-expressed self antigens. In addition to direct depletion of CD4+ regulatory T cells, we have discovered other treatments that induce priming of concomitant immunity. Among these are (1) chemotherapeutic lymphodepletion, (2) stimulation through the TNFR family member GITR, and (3) local expression of GM-CSF. Each of these treatments elicits rejection of secondary tumors in primary tumor-bearing hosts, although the mechanisms by which they function remain unknown. Lymphoablation causes homeostatic proliferation of all lymphoid subsets, but may also have selective effects on regulatory T cells. Likewise, stimulation of GITR has been implicated in both blockade of suppressor function and hyperactivation of CD8 T cells. GM-CSF activated DCs may act directly on regulatory T cells, or may overcome local suppression by direct stimulation of CD8 T cells. Unraveling these mechanisms will provide a solid understanding of methods for breaking immunological tolerance to poorly-immunogenic tumors. We hypothesize that concomitant immunity, characterized by immune recognition of tumor-expressed self antigens, can be induced by elimination of CD4 regulatory T cells and/or by driving expansion of CD8 T cells in hosts with progressive tumors. Specific Aim 1: Determine the mechanism for induction of concomitant immunity in lymphodepleted hosts. Treatment of mice with cyclophosphamide results in massive lymphodepletion and potent concomitant immunity. This is highly schedule dependent, with optimal effects achieved when primary tumor growth and re-population of lymphoid compartments occur simultaneously. This observation, together with a previous report that CD8 homeostatic expansion can lead to immune recognition of tumors, suggests that rapid CD8 proliferation contributes to concomitant immunity. However regulatory T cells are also likely to play a role. We hypothesize that cyclophosphamide elicit concomitant immunity through both depletion of regulatory T cells and the induction of CD8 T cell homeostasis. Specific Aim 2: Determine if concomitant immunity is induced by stimulation of GITR on regulatory T cells and/or on CD8 T cells. Melanoma-bearing hosts treated with stimulatory DTA-1 monoclonal antibody to GITR mount potent concomitant immunity. It was originally described that DTA-1 functions by binding to regulatory T cells and blocking suppressive function, but it is now known that this antibody also binds GITR-expressing activated CD4 and CD8 T cell populations, thereby inducing hyperactivation and proliferation. We hypothesize that DTA-1 induces concomitant immunity through its effects on regulatory T cells and CD8 T cells. Specific Aim 3: Define if tumor GM-CSF production induces concomitant immunity by activating dendritic cells to cross-prime CD8 T cells, and characterize the action of these dendritic cells on regulatory T cells. The predominant effect of tumor GM-CSF expression is the local recruitment of dendritic cells (DC's). DC's may function through one or more pathways. First, they may directly contribute to concomitant immunity by cross-presenting tumor antigens, thus expanding CD8 T cell effectors in draining lymph nodes. Secondly, GM-CSF-recruited dendritic cells may act directly by blocking regulatory T cell function. We hypothesize that, in mice bearing B16-GMCSF tumors, dendritic cells are responsible for local blockade of regulatory T cell function, as well as efficient tumor antigen cross-presentation, and that this combination induces priming of concomitant immunity.