Using a murine cre-lox knockout of CD91 in CD11c+ myeloid cells, Sedlackk et al. observed that the induction of tumors by methylcholantrene (MCA) occurred earlier and more robustly than in control mice. Differences in the infiltrating immune populations were observed at the site of MCA treatment at 2 weeks, but these differences were lost by week 9 or later, suggesting initial differences in immune surveillance while the antigen load was low. The ratio of predicted mutant to native peptide binding affinity to MHC-I correlated with escape from surveillance in CD91 KO mice. In silico analysis of human polymorphisms supported a role for CD91 in T cell infiltration.
The immune system detects aberrant, premalignant cells and eliminates them before the development of cancer. Immune cells, including T cells, have been shown to be critical components in eradicating these aberrant cells, and when absent in the host, incidence of cancer increases. Here, we show that CD91, a receptor expressed on antigen-presenting cells, is required for priming immune responses to nascent, emerging tumors. In the absence of CD91, effector immune responses are subdued, and tumor incidence and progression are amplified. We also show that, consequently, tumors that arise in the absence of CD91 express neo-epitopes with indices that are indicative of greater immunogenicity. Polymorphisms in human CD91 that are expected to affect ligand binding are shown to influence antitumor immune responses in cancer patients. This study presents a molecular mechanism for priming immune responses to nascent, emerging tumors that becomes a predictor of cancer susceptibility and progression.