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Therapeutic Vascular and Immune Normalization in the Melanoma Microenvironment Using STING Agonists

Chelvanambi, Manoj (2021) Therapeutic Vascular and Immune Normalization in the Melanoma Microenvironment Using STING Agonists. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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CD8+ T-cells are indispensable for immune-mediated rejection of solid cancers. Hence, the conditional enhancement of intratumoral T-cell content and/or function defines a preferred outcome for successful immunotherapies. Activated anti-tumor CD8+ T-cells rely on functional blood vessels for their efficient trafficking to, and extravasation into, the tumor parenchyma. Indeed, pathologic progression of solid tumors is closely associated with the development of structurally and functionally abnormal tumor blood vessels which impede T-cell infiltration into cancer lesions. In this regard, therapeutic dosing of anti-angiogenic interventional strategies fortifies or reprograms tumor blood vessels (or vascular normalization) to significantly improve intratumoral CD8+ T-cell infiltration. Intriguingly, agonists of Stimulator of Interferon Genes (STING), which evolved from a class of anti-angiogenic agents, have recently demonstrated significant clinical promise for their ability to enhance CD8+ T-cell recruitment into tumors but whether therapeutic changes to the tumor vasculature underlies successful immune-mediated tumor control remain only partially resolved. Indeed, in this thesis, I demonstrate that intratumoral administration of STING agonist ADU S-100 induces vascular normalization (i.e., improved vascular perfusion, enhanced pericyte coverage and increased endothelial activation) and enhances tumor infiltration by immune cells, specifically, CD8+ T-cells and CD11c+ dendritic cells (DC). STING activation also increases local production of pro-inflammatory cytokines/chemokines that sponsor the development of high endothelial venules (HEV) and HEV-associated tertiary lymphoid structures (TLS) within the therapeutic melanoma tumor microenvironment (TME). HEV/TLS formation with STING agonism was further linked to evidence of local T-cell cross-priming by tumor-resident antigen presenting cells (APC) within the tumor microenvironment (TME), with the therapeutic tumor infiltrating lymphocyte (TIL) repertoire exhibiting enrichment in T cell clonotypes found in the periphery as well as those detected only within the TME. These vasculature-centric underpinnings for the efficacy of STING agonist-based interventions provide enthusiasm for improved translational value of future combinational cancer immunotherapies that seek to integrate these agents.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Chelvanambi, Manojmac392@pitt.edumac3920000-0003-2130-3118
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairButterfield, Lisa
Committee MemberBinder, Robert
Committee MemberFalo, Louis
Committee MemberWatkins, Simon
Thesis AdvisorStorkus, Walter
Date: 13 May 2021
Date Type: Publication
Defense Date: 12 March 2021
Approval Date: 13 May 2021
Submission Date: 25 March 2021
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 166
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: Melanoma, STING, Vascular Normalization, Tertiary lymphoid structures, CD8 T-cells, Dendritic cells
Date Deposited: 14 May 2021 02:00
Last Modified: 14 May 2021 02:00

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