2. Academic Validation
  3. Selective targeting of GARP-LTGFβ axis in the tumor microenvironment augments PD-1 blockade via enhancing CD8+ T cell antitumor immunity

Selective targeting of GARP-LTGFβ axis in the tumor microenvironment augments PD-1 blockade via enhancing CD8+ T cell antitumor immunity

  • J Immunother Cancer. 2022 Sep;10(9):e005433. doi: 10.1136/jitc-2022-005433.
Anqi Li 1 2,  Yuzhou Chang 2 3,  No-Joon Song 2,  Xingjun Wu 2,  Dongjun Chung 2 3,  Brian P Riesenberg 2,  Maria Velegraki 2,  Giuseppe D Giuliani 4 5,  Komal Das 2,  Tamio Okimoto 1,  Hyunwoo Kwon 1 2,  Karthik B Chakravarthy 1 2,  Chelsea Bolyard 2,  Yi Wang 2,  Kai He 2 6,  Margaret Gatti-Mays 2 6,  Jayajit Das 2 7,  Yiping Yang 2 8,  Daniel T Gewirth 9,  Qin Ma 2 3,  David Carbone 2 6,  Zihai Li 10 6
Affiliations

Affiliations

  • 1 College of Medicine, The Ohio State University, Columbus, Ohio, USA.
  • 2 Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center - Arthur G James Cancer Hospital and Richard J Solove Research Institute, The Ohio State University, Columbus, Ohio, USA.
  • 3 Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, Ohio, USA.
  • 4 Battelle Center for Mathematical Medicine, The Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio, USA.
  • 5 Department of Physics, The Ohio State University, Columbus, Ohio, USA.
  • 6 Division of Medical Oncology, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, Ohio, USA.
  • 7 Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio, USA.
  • 8 Division of Hematology, The Ohio State University College of Medicine, Columbus, Ohio, USA.
  • 9 Hauptman-Woodward Medical Research Institute, Buffalo, New York, USA.
  • 10 Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center - Arthur G James Cancer Hospital and Richard J Solove Research Institute, The Ohio State University, Columbus, Ohio, USA [email protected].
PMID: 36096533 DOI: 10.1136/jitc-2022-005433
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.

Keywords

CD8-positive T-lymphocytes; immunotherapy; programmed cell death 1 receptor; transplantation immunology.

Figures
Products