Targeting Endoglin-Expressing Regulatory T Cells in the Tumor Microenvironment Enhances the Effect of PD1 Checkpoint Inhibitor Immunotherapy
| Autor: | Andrew B. Nixon, Madelon Paauwe, Melpomeni Toitou, Charles P. Theuer, Marieke F. Fransen, Marieke C. Barnhoorn, Bryan Koolmoes, Lukas J. A. C. Hawinkels, James C. H. Hardwick, Maaike F.M. Koops, Ricardo A. Angela, Mark J A Schoonderwoerd, Yingmiao Liu, Cornelis F. M. Sier |
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| Přispěvatelé: | Pulmonary medicine, CCA - Cancer biology and immunology |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Cancer Research medicine.medical_treatment Programmed Cell Death 1 Receptor Receptors Fc Biology T-Lymphocytes Regulatory 03 medical and health sciences Mice 0302 clinical medicine Immune system Cell Line Tumor Neoplasms hemic and lymphatic diseases Antineoplastic Combined Chemotherapy Protocols medicine Tumor Microenvironment otorhinolaryngologic diseases Cytotoxic T cell Animals Humans Immune Checkpoint Inhibitors Mice Knockout Tumor microenvironment Endoglin Cancer Antibodies Monoclonal Drug Synergism Immunotherapy medicine.disease Disease Models Animal 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research biology.protein Female Antibody CD8 Signal Transduction T-Lymphocytes Cytotoxic |
| Zdroj: | Schoonderwoerd, M J A, Koops, M F M, Angela, R A, Koolmoes, B, Toitou, M, Paauwe, M, Barnhoorn, M C, Liu, Y, Sier, C F M, Hardwick, J C H, Nixon, A B, Theuer, C P, Fransen, M F & Hawinkels, L J A C 2020, ' Targeting Endoglin-Expressing Regulatory T Cells in the Tumor Microenvironment Enhances the Effect of PD1 Checkpoint Inhibitor Immunotherapy ', Clinical Cancer Research, vol. 26, no. 14, pp. 3831-3842 . https://doi.org/10.1158/1078-0432.CCR-19-2889 Clinical Cancer Research, 26(14), 3831-3842. AMER ASSOC CANCER RESEARCH Clinical Cancer Research, 26(14), 3831-3842. American Association for Cancer Research Inc. |
| ISSN: | 1078-0432 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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