Year: 2014
Type: article
Abstract: Adaptive immune responses against tumors are routinely detected in hosts bearing the tumors. However, the mechanisms of priming T cell responses which are central to the underlying immunosurveillance for nascent tumors remains unclear, given the limited amount of each unique tumor antigens available for cross-priming during the early stages of tumor development and lack of classical PAMPs in general. I provide evidence here that heat shock proteins (HSPs), when released into the tumor microenvironment under these conditions, is the molecular entity necessary for priming specific tumor-associated immunity. These responses require CD91, the endocytic and signaling receptor for the immunogenic HSPs. In this study, I generated CD11c-specific CD91 knockout mice and showed that tumors grew faster in those knockout mice compared to CD91+/+ mice, due to a lack of priming efficient T cell responses. In addition, I 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; second, RAP-expressing tumors, when used as an immunogen in tumor prophylaxis, were significantly less efficient in priming immune responses; third, inhibition of antigen cross-presentation by RAP reduced T cell proliferation in vivo; last, the competition of RAP and tumor-derived HSP for binding to CD91 was examined in vivo. In the presence of RAP, fewer tumor-derived HSPs were taken up by APCs in draining lymph nodes. In summary, this study demonstrates that early in tumor development, the HSP-CD91 pathway is critical for establishment of anti-tumor immunity. Considering that elevated RAP levels have been reported in colon cancer patients, I propose a novel mechanism of immune evasion for tumors expressing competing ligands for immune receptors such as CD91.
Author: Yu Zhou
Language: English
Topic: Heat shock proteins research
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2125201812