Agents of cancer immunosurveillance: HSPs and dsDNA

Abstract

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.

Keywords: CD91/LRP1; STING, IgM; adjuvant; antigen; cGAS; cross-priming; heat shock proteins.

Key Figure, Figure 1.. Model of sensing and elimination of emerging tumors by the mammalian immune system.

(A) Tumor-derived molecular stimuli can provide adjuvanticity that is necessary for priming and activating anti-tumor T cell and NK cell responses during cancer immunosurveillance. Tumor cell death leads to the release of HSPs[5,13,16] and dsDNA[56]. (i) Tumor-derived HSPs bind to CD91 expressed on DCs and undergo endocytosis along with the chaperoned peptides[–23]. Peptides are processed and presented by MHC I and MHC II[9,35,72]. Upon binding HSPs, CD91 is phosphorylated and initiates signaling pathways within the DC leading to upregulation of CD86 and CD40, the release of cytokines, and maturation of DCs[,–23,75]. (ii) dsDNA binds to cGAS in DCs after internalization[55,56]. dsDNA may bind cGAS in the tumor cell itself and cGAMP can transport into DCs via gap junctions[52,54]. cGAS activates STING in the DC leading to upregulation of CD28, release of cytokines, and maturation of DCs[–45,51,52]. Mature DCs migrate to lymph nodes where they prime naïve CD8⁺ and CD4⁺ T cells to become anti-tumor effector T cells. Mature DCs can also activate NK cells via cytokines[31,53,54]. Effector T cells and activated NK cells mediate cancer cell death.

Figure I in Box 3.

Natural IgM as an alternative pathway for cancer immunosurveillance.