Zhou, Yu 'Jerry'
(2014)
The role of heat shock protein receptor CD91 in initiation of tumor associated immunity.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
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.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
25 March 2014 |
| Date Type: |
Publication |
| Defense Date: |
12 February 2014 |
| Approval Date: |
25 March 2014 |
| Submission Date: |
24 March 2014 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
111 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Tumor immunology, Immunosurveillance, Heat Shock Protein, CD91/LRP-1, RAP, Antigen transfer |
| Date Deposited: |
25 Mar 2014 17:34 |
| Last Modified: |
19 Dec 2016 14:41 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/20821 |
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