Selective targeting of GARP-LTGFβ axis in the tumor microenvironment augments PD-1 blockade via enhancing CD8+ T cell antitumor immunity. Issue 9 (12th September 2022)

• Record Type: Journal Article
• Authors: Li, Anqi; Chang, Yuzhou; Song, No-Joon; Wu, Xingjun; Chung, Dongjun; Riesenberg, Brian P; Velegraki, Maria; Giuliani, Giuseppe D; Das, Komal; Okimoto, Tamio; Kwon, Hyunwoo; Chakravarthy, Karthik B; Bolyard, Chelsea; Wang, Yi; He, Kai; Gatti-Mays, Margaret; Das, Jayajit; Yang, Yiping; Gewirth, Daniel T; Ma, Qin; Carbone, David; Li, Zihai
• Is Part Of: Journal for immunotherapy of cancer. Volume 10:Issue 9(2022)
• Publication Date: 2022-09-12
• Subjects: immunotherapy -- CD8-positive T-lymphocytes -- programmed cell death 1 receptor -- transplantation immunology; Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1136/jitc-2022-005433
• Languages: English
• ISSNs: 2051-1426

Abstract

Abstract : Background: Immune checkpoint blockade (ICB) has revolutionized cancer immunotherapy. However, most patients with cancer fail to respond clinically. One potential reason is the accumulation of immunosuppressive transforming growth factor β (TGFβ) in the tumor microenvironment (TME). TGFβ drives cancer immune evasion in part by inducing regulatory T cells (Tregs) and limiting CD8 + T cell function. Glycoprotein-A repetitions predominant (GARP) is a cell surface docking receptor for activating latent TGFβ1, TGFβ2 and TGFβ3, with its expression restricted predominantly to effector Tregs, cancer cells, and platelets. Methods: We investigated the role of GARP in human patients with cancer by analyzing existing large databases. In addition, we generated and humanized an anti-GARP monoclonal antibody and evaluated its antitumor efficacy and underlying mechanisms of action in murine models of cancer. Results: 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 report on a unique anti-human GARP antibody (named PIIO-1) that specifically binds the ligand-interacting domain of all latent TGFβ isoforms. PIIO-1 lacks recognition of GARP-TGFβ complex on platelets. Using human LRRC32 (encoding GARP) knock-in mice, we find that PIIO-1 does not cause thrombocytopenia; is preferentially distributed in the TME; and exhibits therapeutic efficacy against GARP + and GARP - cancers, alone or in combination with anti-PD-1 antibody. Mechanistically, PIIO-1 treatment reduces canonical TGFβ signaling in tumor-infiltrating immune cells, prevents T cell exhaustion, and enhances CD8 + T cell migration into the TME in a C-X-C motif chemokine receptor 3 (CXCR3)-dependent manner. Conclusion: GARP contributes to multiple aspects of immune resistance in cancer. Anti-human GARP antibody PIIO-1 is an efficacious and safe strategy to block GARP-mediated LTGFβ 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.