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Selective Targeting of GARP-TGFbeta axis for Cancer Immunotherapy

Li, Anqi
http://rave.ohiolink.edu/etdc/view?acc_num=osu1669841700183272

Abstract Details

2022, Doctor of Philosophy, Ohio State University, Biomedical Sciences.
Immune checkpoint blockade (ICB) has revolutionized cancer immunotherapy for decades. However, most cancer patients fail to respond clinically which raised the importance of investigating long-lasting, uniformly beneficial therapeutics. One prospect for improving patients’ responsiveness is the combination of ICB with targeting its resistance factors. One potential reason is the accumulation of immune suppressive transforming growth factor-beta (TGFbeta) in the tumor microenvironment (TME). TGFbeta drives cancer immune evasion in part by inducing regulatory T cells (Tregs) and limiting CD8+ T cell function. Glycoprotein-A repetitions predominant (GARP, which is encoded by Lrrc32, leucine rich repeat containing 32) is a cell surface docking receptor for activating latent TGFbeta1, 2, and 3, with its expression in effector Tregs, cancer cells as well as platelets majorly. Our previous work underlined the role of GARP on platelets and Tregs as major resources of active TGFbeta devoted to the immune suppression in the TME. Depleting GARP from platelets or Tregs genetically delayed tumor growth by controlling TGFbeta in the TME hence improving anti-tumor immunity. We hypothesized GARP, specifically on Treg cells, acts as the mechanism of immune suppression and ICB resistance in the TME by supplying active TGFbeta. We examine this hypothesis in two aspects 1) how GARP on Tregs regulates CD8+ T cell effector function as well as exhaustion in the TME and 2) selective targeting GARP-TGFbeta axis as a potential therapeutic in combination with PD1 blockade. We found improved tumor control in the Treg-specific GARP depletion model was associated with the less suppressive ability of Tregs and reduced CD8+ T cell exhaustion. The generation of CD25-Foxp3+ Treg cells limited Treg suppressive phenotype by reducing the expression of suppressive molecules. Enhanced anti-tumor immunity in CD8+ T cells was reflected by less exhausted phenotype and elevated effector cytokines production in the murine urothelial carcinoma model. Therefore, we generated and humanized an anti-GARP monoclonal antibody and evaluated its anti-tumor efficacy and underlying mechanisms of action in murine models of cancer. We reported on a unique anti-human GARP antibody (named PIIO-1) that specifically binds the ligand-interacting domain of all latent TGFbeta isoforms. In addition, PIIO-1 lacks recognition of the GARP-TGFbeta complex on platelets but is able to bind to GARP on Treg cells. Using human LRRC32 knock-in mice, we demonstrate that PIIO-1 does not cause thrombocytopenia; it is preferentially distributed in the TME and its draining lymph node. PIIO-1 treatment reduces canonical TGFbeta signaling in tumor-infiltrating immune cells, prevents T cell exhaustion, and enhances CD8+ T cell migration into the TME in a CXCR3-dependent manner, therefore controlling GARP- tumor growth. We then investigated the role of GARP in human cancer patients by analyzing existing databases for evidence of potential in combining PD-1 ICB with targeting the GARP-TGFbeta axis. We demonstrate that GARP overexpression in human cancers correlates with a tolerogenic TME and poor clinical response to ICB, suggesting GARP blockade may improve cancer immunotherapy. We showed therapeutic efficacy against both GARP+ and GARP- cancers in combination with the anti-PD-1 antibody. GARP contributes to multiple aspects of immune resistance in cancers. Anti-GARP antibody PIIO-1 is an efficacious and safe strategy to block GARP-mediated LTGFbeta activation, enhance CD8+ T cell trafficking and functionality in the tumor, and overcome primary resistance to anti-PD-1 ICB. PIIO-1, therefore, warrants clinical development as a novel cancer immunotherapeutic.
Zihai Li (Advisor)
Christin Burd (Committee Member)
Yiping Yang (Committee Member)
Dean Lee (Committee Member)
Hazem Ghoneim (Committee Member)
163 p.
Biomedical Research; Immunology
GARP, Cancer Immunotherapy, ICB resistance, Tregs, TGFbeta

Recommended Citations

Citations

  • Li, A. (2022). Selective Targeting of GARP-TGFbeta axis for Cancer Immunotherapy [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1669841700183272

    APA Style (7th edition)

  • Li, Anqi. Selective Targeting of GARP-TGFbeta axis for Cancer Immunotherapy. 2022. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1669841700183272.

    MLA Style (8th edition)

  • Li, Anqi. "Selective Targeting of GARP-TGFbeta axis for Cancer Immunotherapy." Doctoral dissertation, Ohio State University, 2022. http://rave.ohiolink.edu/etdc/view?acc_num=osu1669841700183272

    Chicago Manual of Style (17th edition)

osu1669841700183272
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This open access ETD is published by The Ohio State University and OhioLINK.