Abstract Immunosurveillance mechanisms in tissues eliminates pre-cancerous cells prior to formation of malignancies. This is supported by evidence from immunodeficient individuals where a much higher incidence of a variety of cancers have been reported compared with their immunocompetent counterparts. Empirical evidence from mice shows that effector mechanisms responsible for eliminating these emerging, nascent tumors primarily involve T cells and NK cells. In humans and mice, deficiencies in T cells numbers and/or molecules associated with T cell function such as STAT1, IFNγR1 or perforin, render hosts much more susceptible to developing cancers than immunocompetent individuals. How emerging, nascent tumors prime T cell responses has until recently remained an enigma and a major gap in knowledge. The Binder lab recently uncovered a pathway involving tumor-derived HSPs and the receptor CD91 expressed on APCs, that leads to priming of T cell responses to emerging, nascent tumors. In mice or humans with deficiencies of CD91 function in DC, T cell responses to nascent tumors are poorer than in mice/humans without CD91 deficiencies, allowing for the emergence of tumors. Our prior work has shown mechanistically that engagement of CD91 on APCs by tumor-derived HSPs leads to cross-presentation of HSP-chaperoned peptides (signal 1), and activation of signaling networks that provides co-stimulation (signal 2) and cytokines (signal 3). These three signals are essential for priming T cell responses and HSPs prime robust T cell responses in mice and humans. Our hypothesis is that tumor-derived HSPs deliver a signal to CD91 on APCs allowing for provision of co-stimulation and cytokines for T cell-mediated cancer immunosurveillance. We have previously shown in macrophages and DCs that two Tyrosines in the cytoplasmic tail of CD91 are important in initiating signaling pathways for cytokine elaboration and co-stimulation. In this proposal we will develop a new mouse model that conditionally expresses a non-signaling CD91 construct, to test the importance of CD91-mediated signaling in response to tumor-derived HSPs in the context of cancer immunosurveillance. Importantly, we shall use this mouse model to distinguish the role of CD91 in provision of co-stimulation from its other functions related to cancer immunosurveillance.

Immunosurveillance mechanisms detect and eliminate nascent, emerging tumors in tissues. We have identified a role for the heat shock protein (HSP) receptor CD91 as a central player for priming immune responses to tumors. In this proposal, we investigate the function of CD91 in relation to these immune responses. By understanding this immunological pathway we will solve an outstanding question of how tumors prime immune responses, one that is central to cancer immunology. We will also be able to determine which individuals have poor CD91 function and are therefore more susceptibility to developing cancer.