VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer.

By M. Terme, S. Pernot, E. Marcheteau, Federico Sandoval, N. Benhamouda, O. Colussi, O. Dubreuil, A. Carpentier, E. Tartour, J. Taieb. Cancer Research, 2013

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Multitarget antiangiogenic tyrosine kinase inhibitors (TKI) have been shown to reduce regulatory T cells (Treg) in tumor-bearing animals and patients with metastatic renal carcinomas. However, a direct role of the VEGF-A/VEGFR pathway inhibition in this phenomenon is a matter of debate and molecular mechanisms leading to Treg modulation in this setting have not been explored to date. Treg proportion, number, and proliferation were analyzed by flow cytometry in peripheral blood of patients with metastatic colorectal cancer (mCRC) treated with bevacizumab, a monoclonal antibody targeting specifically VEGF-A, and in colon cancer-bearing mice (CT26) treated with drugs targeting the VEGF/VEGFR axis. The direct impact of VEGF-A on Treg induction was assessed together with specific blockade of different isoforms of VEGFRs that may be involved. In CT26-bearing mice, anti-VEGF antibody and sunitinib treatments reduced Treg but masitinib, a TKI not targeting VEGFR, did not. Targeting VEGF-A/VEGFR axis seems sufficient to affect Treg percentages, without any changes in their function. Similarly, bevacizumab inhibited Treg accumulation in peripheral blood of patients with mCRCs. In vitro, Treg expressing VEGFR from tumor-bearing mice directly proliferated in response to VEGF-A. Anti-VEGF-A treatment decreased Treg proliferation in mice as well as in patients with mCRCs. VEGFR-2- but not VEGFR-1-specific blockade led to the same results. We identified a novel mechanism of tumor escape by which VEGF-A directly triggers Treg proliferation. This proliferation is inhibited by VEGF-A/VEGFR-2 blockade. Anti-VEGF-A therapies also have immunologic effects that may be used with a therapeutic goal in the future.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/4c7785d89dc5adcde00625fa27f0e2e13b8510ca

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Citations in the corpus

Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents. (2015, background): “Immunological Effects of Targeted Anticancer Agents Agent Setting Effect Notes Reference Bevacizumab transplantable murine CRC depletes TREG cells mechanism involving KDR Terme et al., 2013 Dasatinib CML favors the expansion of circulating CTLs and NK cells correlates with molecular response to chem”
T Cell Dysfunction in Cancer (2018, background): “VEGF secretion has been found to affect T cell functionality both directly and indirectly, via suppression of DC maturation and recruitment of suppressive cell populations (Gabrilovich et al., 1998; Terme et al., 2013).”
Vascular normalization as an emerging strategy to enhance cancer immunotherapy (2013, positive): “Importantly, this systemic immunosuppression induced by excess VEGF can be reversed by the blockade of VEGF/VEGFR2 signaling pathway (13, 21, 24).”