Inhibition of the Heat Shock Protein receptor CD91 abrogates concomitant anti-tumor immunity (P2035)

Abstract

Abstract Immunosurveillance mechanisms of tumors depend on the host’s ability to efficiently cross-present tumor antigens. We provide evidence here that heat shock proteins (HSPs), when released into the tumor microenvironment, is the antigen carrier necessary for priming concomitant tumor specific immunity. These responses require CD91- the endocytic and signaling receptor for the immunogenic HSPs. In our study, we generated CD11c-specific CD91 knockout mice and showed that tumors grew faster in those mice, compared to CD91+/+ mice. In addition, we abrogated the interaction of tumor-derived HSP with CD91 in vivo by over-expression of Receptor Associated Protein (RAP), an endogenous CD91 antagonist. The data showed that: first, tumors expressing RAP grew with significantly faster kinetics than the non-RAP expressing counterparts in wild type mice, although this difference was non-existent in immunocompromised mice; second, RAP-expressing tumors, when used as an immunogen in tumor prophylaxis, were significantly less efficient in priming immune responses; third, in the presence of RAP, less amount of tumor-derived EGFP-labeled HSPs were taken up by APCs in draining lymph nodes. In summary, our study demonstrates that the HSP-CD91 pathway is critical for establishment of concomitant immunity. Considering that elevated RAP levels have been reported in cancer patients, we propose a novel mechanism of immune evasion for tumors expressing competing ligands for immune receptors such as CD91.