Targeting Endoglin-Expressing Regulatory T Cells in the Tumor Microenvironment Enhances the Effect of PD1 Checkpoint Inhibitor Immunotherapy.

Abstract

PURPOSE:

Endoglin is a coreceptor for TGFβ ligands that is highly expressed on proliferating endothelial cells and other cells in the tumor microenvironment. Clinical studies have noted increased programmed cell death (PD)-1 expression on cytotoxic T cells in the peripheral blood of patients with cancer treated with TRC105, an endoglin-targeting antibody. In this study, we investigated the combination of endoglin antibodies (TRC105 and M1043) with an anti-PD1 antibody.

EXPERIMENTAL DESIGN:

The combination anti-endoglin/anti-PD1 antibodies was tested in four preclinical mouse models representing different stages of cancer development. To investigate the underlying mechanism, Fc-receptor-knockout mice were used complemented with depletion of multiple immune subsets in mice. Tumor growth and the composition of immune infiltrate were analyzed by flow cytometry. Finally, human colorectal cancer specimens were analyzed for presence of endoglin-expressing regulatory T cells (Treg).

RESULTS:

In all models, the combination of endoglin antibody and PD1 inhibition produced durable tumor responses, leading to complete regressions in 30% to 40% of the mice. These effects were dependent on the presence of Fcγ receptors, indicating the involvement of antibody-dependent cytotoxic responses and the presence of CD8+ cytotoxic T cells and CD4+ Th cells. Interestingly, treatment with the endoglin antibody, TRC105, significantly decreased the number of intratumoral Tregs. Endoglin-expressing Tregs were also detected in human colorectal cancer specimens.

CONCLUSIONS:

Taken together, these data provide a rationale for combining TRC105 and anti-PD1 therapy and provide additional evidence of endoglin's immunomodulatory role.

• Authors: Mark J A Schoonderwoerd, Maaike F M Koops, Ricardo A Angela, Bryan Koolmoes, Melpomeni Toitou, Madelon Paauwe, Marieke C Barnhoorn, Yingmiao Liu, Cornelis F M Sier, James C H Hardwick, Andrew B Nixon, Charles P Theuer, Marieke F Fransen, Lukas J A C Hawinkels
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 26 Issue 14 Pg. 3831-3842 (07 15 2020) ISSN: 1557-3265 [Electronic] United States
• PMID: 32332012 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal
• ENG protein, human
• Endoglin
• Eng protein, mouse
• Immune Checkpoint Inhibitors
• Pdcd1 protein, mouse
• Programmed Cell Death 1 Receptor
• Receptors, Fc
• carotuximab

Topics

• Animals
• Antibodies, Monoclonal (pharmacology, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Cell Line, Tumor (transplantation)
• Disease Models, Animal
• Drug Synergism
• Endoglin (antagonists & inhibitors, metabolism)
• Female
• Humans
• Immune Checkpoint Inhibitors (pharmacology, therapeutic use)
• Male
• Mice
• Mice, Knockout
• Neoplasms (drug therapy, immunology, pathology)
• Programmed Cell Death 1 Receptor (antagonists & inhibitors)
• Receptors, Fc (genetics)
• Signal Transduction (drug effects, immunology)
• T-Lymphocytes, Cytotoxic (drug effects, immunology)
• T-Lymphocytes, Regulatory (drug effects, immunology, metabolism)
• Tumor Microenvironment (drug effects, immunology)