Regulation of dendritic cell functions by CD91 and its ligand heat shock proteins during immunosurveillance of emerging tumors

Nayak, Devanshi A. (2025) Regulation of dendritic cell functions by CD91 and its ligand heat shock proteins during immunosurveillance of emerging tumors. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

During cancer immunosurveillance, dendritic cells (DCs) play a central role in orchestrating T cell responses against emerging tumors. Capture of miniscule amounts of antigen along with tumor-derived costimulatory signals can drive maturation and activation of DCs. Expression of the heat shock protein receptor CD91 on DCs is essential in the cross-priming of T cell responses in the context of nascent tumors. There are multiple DC and macrophage subsets that express CD91 and engage tumor-derived gp96 to initiate anti-tumor immune responses, yet the specific CD91+ APCs that are required for efficient T cell cross-priming during cancer immunosurveillance are unknown. We determined that CD91 expression on type 1 conventional DCs is necessary for cancer immunosurveillance, specifically for capture of CD91 ligand, gp96. However, gp96+ cDC1 only facilitate early tumor control, while sustained and long-term tumor rejection is bestowed to the host by other gp96+ cross-priming DCs following intercellular transfer of gp96 between migratory and resident APCs and specific T cell activation. We show the CD91-induced transcriptome in APCs promotes cross-priming of T cell responses while downregulating immune regulatory pathways. Our results show an elaborate and synchronized division of labor amongst APCs for the successful elimination of cancer cells. The specialized functions of APC subsets can be coordinately harnessed for effective immunotherapy of cancer.

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Details

Item Type:	University of Pittsburgh ETD
Status:	Unpublished
Creators/Authors:	Creators Email Pitt Username ORCID Nayak, Devanshi A. den33@pitt.edu den33 0000-0002-7897-0758
ETD Committee:	Title Member Email Address Pitt Username ORCID Committee Chair Storkus, Walter J. storkuswj@upmc.edu Committee Member Bruno, Tullia C. tbruno@pitt.edu Committee Member Lohmueller, Jason lohmuellerj@upmc.edu Committee Member Kaplan, Daniel H. dankaplan@pitt.edu Thesis Advisor Binder, Robert J. rjb42@pitt.edu
Date:	23 January 2025
Date Type:	Publication
Defense Date:	13 September 2024
Approval Date:	23 January 2025
Submission Date:	4 December 2024
Access Restriction:	No restriction; Release the ETD for access worldwide immediately.
Number of Pages:	130
Institution:	University of Pittsburgh
Schools and Programs:	School of Medicine > Microbiology and Immunology
Degree:	PhD - Doctor of Philosophy
Thesis Type:	Doctoral Dissertation
Refereed:	Yes
Uncontrolled Keywords:	Cancer immunosurveillance, antigen presenting cells, heat shock proteins
Date Deposited:	23 Jan 2025 20:05
Last Modified:	23 Jan 2025 20:05
URI:	http://d-scholarship.pitt.edu/id/eprint/47158

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