Killer cell lectin-like receptor G1 (KLRG1) as a novel target for checkpoint blockade therapy

Tata, Angela Lynn

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Overview

Year:: 2021
Contributor:: Tata, Angela Lynn (creator); Brossay, Laurent (Advisor); Vaishnava, Shipra (Reader); Bowen, Wayne (Reader); Fast, Loren (Reader); Wands, Jack (Reader); Campbell, Kerry (Reader); Brown University. Department of Molecular Biology, Cell Biology and Biochemistry (sponsor)
Genre:: theses
Subject:: Immunology; Killer cells; Cancer; Cytomegalovirus infections; Immunotherapy; Cancer--Immunotherapy; Innate immunology; Killer cell lectin-like receptor G1 (KLRG1); Programmed cell death protein-1 (PD-1)
Extent:: xiii, 223 p.

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Description

Abstract:: Checkpoint blockade therapy, which targets conserved negative regulators of immune cell activation that act as “checkpoint molecules” that govern the balance between inhibition and hyperactivation states, has become an incredibly important area of immunology research. The most well-known checkpoint inhibitor target, Programmed cell death protein-1 (PD-1), has been extensively shown to block T cell activation and lead to T cell exhaustion. And while PD-1 blockade therapy has had great success in a treating a number of different cancers and viral infections, there are still a large portion of patients who either do not respond to current therapy or demonstrate immune escape, raising the need for the identification of new checkpoint inhibitor targets that can be used alone and in combination with PD-1 therapy. The work presented here examines the role of the inhibitory receptor KLRG1 in the immune response to challenge and determines the efficacy of KLRG1 as a checkpoint target for immunotherapy. KLRG1 is a well conserved C-type lectin receptor expressed on NK cells and CD8+ T cells and has been shown to inhibit immune cell cytokine production, proliferative capacity, and cytotoxicity. We found that KLRG1 is upregulated on both NK cells and CD8+ T cells during cancer growth and viral infection, making it an intriguing target for checkpoint blockade therapy. We also found that KLRG1 blockade can decrease metastic tumor growth and can synergize with PD-1 blockade to increase anti-tumor immunity by increasing the presence of immune cells within the tumor microenvironment. We also characterized the role of the KLRG1 and PD-1 signaling during acute Murine Cytomegalovirus (MCMV) infection. While KLRG1 blockade did not appear to play a role in the immune response to acute MCMV infection, PD-1 may impact immune cell function after MCMV infection. Overall, this research adds to the field’s knowledge of the role KLRG1 plays during immune challenge and provides a new checkpoint inhibitor target for immunotherapy.
Notes:: Thesis (Ph. D.)--Brown University, 2021

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Citation

Tata, Angela Lynn, "Killer cell lectin-like receptor G1 (KLRG1) as a novel target for checkpoint blockade therapy" (2021). Molecular Biology, Cell Biology, and Biochemistry Theses and Dissertations. Brown Digital Repository. Brown University Library. https://repository.library.brown.edu/studio/item/bdr:mk3xwraj/

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Molecular Biology, Cell Biology, and Biochemistry Theses and Dissertations

Theses and Dissertations for the Molecular Biology, Cell Biology, and Biochemistry department.
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