Identifying Antigen Presenting Cells Responsible for Heat Shock Protein-Mediated Cancer Immunosurveillance

Abstract

Abstract The immune system detects and eliminates nascent, emerging tumor cells. This is mediated primarily by T cells and NK cells. However, the mechanisms that allow efficient T cell priming during cancer immunosurveillance, which is characterized by limited antigen availability, remain unclear. Immunogenic heat shock proteins (HSPs) such as gp96 chaperones minute levels of antigens, in the form of peptides, and allows these to be efficiently cross-presented by APCs, a process that involves the HSP receptor, CD91. Further, engagement of CD91 by HSPs initiates signals for co-stimulation and cytokine production which are necessary for priming anti-tumor responses. We previously showed that mice deficient in CD91 expression in APCs (CD91fl/flCD11cCre) are more susceptible to chemically induced tumors compared to wildtype littermates. Tumors that emerge in these mice prime poorer T cell responses and are less infiltrated than tumors in wildtype mice. The CD91+ APC subset(s) that are responsible for HSP-mediated T cell priming have not been elucidated. This study seeks to define the APC subset(s) necessary for CD91-mediated immune responses in the tumor microenvironment and tumor-draining lymph nodes. Using genetically tagged HSPs, we track the dispersal of tumor-derived HSPs throughout the myeloid system. We show that HSPs are taken up by multiple DC and macrophage subsets. We identify APC subsets that are responsible for HSP-mediated priming of anti-tumor T cell responses, by adoptive transfer of APCs that acquire tumor-derived HSPs. These studies provide an underlying mechanism of how the immune responses to nascent tumors are initiated. They will also have significant implications for cancer prognosis and therapy. Supported by NIH (R01 CA233803)