Agents of cancer immunosurveillance: HSPs and dsDNA

Tumor immunosurveillance requires tumor cell-derived molecules to initiate responses through corresponding receptors on antigen presenting cells (APCs) and a specific effector response designed to eliminate the emerging tumor cells. This is supported by evidence from immunodeficient individuals and experimental animals. Recent discoveries suggest that adjuvanticity of tumor-derived heat shock proteins (HSPs) and double-stranded DNA (dsDNA) are necessary for tumor-specific immunity. There is also the obligatory early transfer of tumor antigens to APCs. We argue that tumor-derived HSPs deliver sufficient chaperoned antigen for cross-priming within the quantitative limits set by nascent tumors. In contrast to late-stage tumors, we are only just beginning to understand the unique interactions of the immune system with precancerous/nascent neoplastic cells, which is important for improved cancer prevention measures. Tumor-derived heat shock proteins (HSPs) and double-stranded DNA (dsDNA) are self-derived mammalian molecules that can provide adjuvanticity necessary to initiate adaptive immune responses.We propose that the receptors for HSPs and dsDNA, which are CD91 and stimulator of interferon genes (STING), respectively, may play a crucial role in cancer immunosurveillance; their loss, dysfunction, or inhibition allows for an increased incidence of cancer in mice and humans.Tumor antigens chaperoned by HSPs are crosspresented by dendritic cells via CD91 to prime T cell responses. Estimates of the amount of chaperoned antigen and HSPs satisfies the quantitative limits available in nascent, emerging tumors and we argue that this strongly supports such a mechanism as a likely important crosspresenting pathway in cancer immunosurveillance.