The immune system recognizes aberrant cells and eliminates them prior to emergence of nascent tumors. This prevents progression of many malignancies. In the absence of such immunity in mice or humans, multiple and frequent tumors are generated. Current immunosurveillance model involves the priming of T cell and NK cell immunity. The gap in knowledge in this model is raised in two questions; (1) What is the molecular mechanism for cross-priming T cell responses in the context of the negligible amount of antigen available at the early stages of nascent tumor development? (2) What is the stimuli for co-stimulation of T cell priming and activation of NK cells. Our work has demonstrated that tumor-derived heat shock proteins (HSPs), introduced during vaccination, are super-efficient at cross-presentation of limited amounts of their chaperoned tumor (peptide) antigen. HSPs are also capable of initiating signals for co-stimulation. Both events require the HSP receptor, CD91, expressed on dendritic cells and together allow for priming potent tumor-specific T cells. The release of cytokines by DCs stimulated with HSPs enhances the T cell responses and activates NK cells. Our hypothesis is that when tumor antigen levels are limiting, as in nascent emerging tumors, the HSP-CD91 pathway is essential for cross-priming of anti-tumor immune responses. In humans, immune responses to cancer are influenced by variable expression levels of CD91 and its polymorphism, driving the clinical and translational relevance of this proposal. In this application we will determine how CD91 serves as an essential conduit for initiating responses for cancer immunosurveillance.
We have identified a role for the heat shock protein (HSP) receptor CD91 in initiation of immune responses against nascent, emerging tumors. These immune responses are central for immunosurveillance of cancer, a concept proposed over a hundred years ago. In this proposal we aim to examine the interaction of CD91 with its ligands, the HSPs, on hematopoietic cells in situ as the mechanism that leads to productive anti-tumor immune responses. By understanding this immunological pathway we will solve an outstanding question that is central to cancer immunology and also be better able to predict individuals that have poor CD91 function and are more susceptibility to developing cancer.
