Inhibition of the Heat Shock Protein receptor CD91 abrogate concomitant anti-tumor immunity (127.24)

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. Our study abrogates the interaction of tumor-derived HSP with CD91 in vivo by over-expression of a natural inhibitor of CD91. The data shows that: first, tumors expressing CD91 inhibitor grew with significantly faster kinetics than the non-inhibitor 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 inhibitor were identical; second, inhibitor-expressing tumors, when used as an immunogen in tumor prophylaxis, were significantly less efficient in priming immune responses. We also examined the competition for CD91 between the inhibitor and tumor-derived HSP in vivo. In summary, our study demonstrates that the HSP-CD91 pathway is critical for establishment of concomitant immunity. We propose a novel mechanism of immune evasion for tumors expressing competing ligands for immune receptors such as CD91.