Abstract A55: Inhibition of the heat shock protein receptor CD91 abrogates concomitant antitumor immunity.

Abstract

Abstract Most tumors are capable of generating immune response in the bearing host, a phenomenon described as concomitant immunity. Since tumors lack the typical (foreign) PAMPs that provide signal 2 for T cell priming, the mechanism of how concomitant immunity is established remains a mystery. We provide evidence here that, heat shock proteins (HSPs), when released into the tumor microenvironment, is the immunogen 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 knockout 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 inhibitor of CD91. 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 and the inherent proliferative rates of tumors with or without RAP were identical; second, RAP-expressing tumors, when used as an immunogen in tumor prophylaxis, were significantly less efficient in priming immune responses; third, we examined the competition for CD91 between RAP and tumor-derived HSP in vivo. 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 colon cancer patients, we propose a novel mechanism of immune evasion for tumors expressing competing ligands for immune receptors such as CD91. Citation Format: Yu Jerry Zhou, Robert J. Binder. Inhibition of the heat shock protein receptor CD91 abrogates concomitant antitumor immunity. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A55.