Despite the ability of the adaptive immune system to distinguish subtle differences between self and non-self antigens, cancers grow and disseminate in their hosts. Using models of allogeneic tumors, which, like transplanted allogeneic organs and tissues, are rejected by the host's adaptive immune system, it was discovered that naturally-occurring IgG antibodies initiate allogeneic tumor rejection. Applying these findings to syngeneic and autologous tumors, allogeneic IgG, when applied in the proper stimulatory context, has been shown to be capable of driving dendritic cell uptake of tumor antigens and systemic T cell-mediated eradication of both primary tumors and distant untreated tumors and metastases, and key aspects of this mechanism have been demonstrated to be conserved in humans. These data represent a promising new cancer immunotherapeutic approach. The objectives of this project are to develop a detailed understanding of the mechanisms responsible for the capacity of naturally occurring tumor-binding allogeneic IgG to eradicate tumors. The hypothesis is that allogeneic IgG and the elicited T cells do not recognize the same antigens, and that while any antibody that binds tumor cells at sufficient levels is capable of activating dendritic cell-mediated T cell immunity, the T cell response converges upon common tumor antigens sufficient to drive tumor eradication. Thus, utilizing mouse models of melanoma, the aims of this project are twofold: 1) to determine the identity and tissue distribution of the melanoma antigens recognized by allogeneic IgG, and 2) to analyze the specificity, phenotype, and function of T cells elicited by allogeneic IgG therapy. Toward these ends, the antigens bound by allogeneic IgG will be identified by mass spectrometry proteomic approaches, assessed for expression on normal tissues, and therapeutically targeted with monoclonal antibodies. Similarly, the T cell clones elicited by allogeneic IgG therapy will be assessed with a statistical framework utilizing combinatorial sampling and cloud computing to determine convergent groups of clones recognizing common antigens, screened to identify the antigens recognized, studied to determine in vivo phenotype, and tested for anti-tumor function. These studies will provide a detailed understanding of the mechanism of allogeneic IgG therapy, establishing a foundation of knowledge to inform future efforts to translate allogeneic IgG therapy to the clinic, and they will also provide biological insight into the systemic coordinationof tumor-specific T cells during a tumor-eradicating response.
In this proposal, we will examine the method by which a new cancer immunotherapy, which uses antibodies to induce the immune system to target and eliminate tumors, generates these effective responses. We will identify the specific molecules targeted both by the antibodies and by the responding immune cells and test which of these molecules are responsible for tumor eradication. This will provide a fundamental understanding of this new therapy, which has the potential to treat a wide variety of cancers.
|Carmi, Yaron; Prestwood, Tyler R; Spitzer, Matthew H et al. (2016) Akt and SHP-1 are DC-intrinsic checkpoints for tumor immunity. JCI Insight 1:e89020|