174O - VEGF-A-induced TREG proliferation, a novel mechanism of tumor immune escape in colorectal cancer: effects of anti-VEGF/VEGFR therapies

Date 29 September 2012
Event ESMO Congress 2012
Session Biomarkers in breast and colorectal cancer
Topics Biomarkers
Colon Cancer
Rectal Cancer
Presenter Magali Terme
Authors M. Terme1, S. Pernot2, E. Marcheteau2, O. Colussi2, F. Sandoval2, N. Benhamouda2, E. Tartour2, J. Taieb2
  • 1Inserm U970 - Parcc, INSERM U970, Paris/FR
  • 2Parcc-european Georges Pompidou Hospital, INSERM U970, Paris/FR

Abstract

Background

Regulatory T cells (Treg) are suspected of hindering an effective antitumor immune response in cancer. Multi-target anti-angiogenic tyrosine kinase inhibitors (TKI) that are routinely used as first or second line treatment of cancer patients, have been shown to decrease Treg proportion in tumor-bearing mice and metastatic renal cancer patients. However, the role of VEGF/VEGFR blockade in this effect is still debatable, and the direct impact of VEGF-A on Treg has not been studied.

Methods

Treg proportion, number were analyzed by flow cytometry in peripheral blood of metastatic colorectal cancer (mCRC) patients treated with bevacizumab, and in CT26 tumor-bearing mice treated with drugs targeting the VEGF axis. The direct impact of VEGF on Treg increase in cancer was also studied.

Results

Sunitinib (a TKI targeting VEGFR, PDGFR, c-kit), and anti-VEGF-A antibody both decreased Treg in CT26 tumor-bearing mice. Masitinib, a TKI that does not target VEGFR, did not reduce Treg proportion in CT26 bearing mice. Bevacizumab, an anti-VEGF-A monoclonal antibody, reduced Treg proportion in peripheral blood of mCRC patients. Proliferation of Treg was enhanced in CT26 tumor-bearing mice compared to tumor-free mice and was decreased after anti-VEGF-A treatment. Furthermore, in vitro experiments have shown that VEGF-A could directly induce Treg proliferation. VEGFR1 and 2 were expressed on Treg in the presence of a tumor. Anti-VEGFR2 antibody administration reduces Treg proportion and also proliferation in CT26 bearing mice, but anti-VEGFR1 antibody did not, suggesting that VEGF-A-induced Treg proliferation was dependent on VEGFR2 expression. In metastatic CRC patients, Treg proliferation was also enhanced compared to healthy volunteers and was blocked by bevacizumab treatment.

Conclusions

We identified a new mechanism by which VEGF-A induced by the tumor could stimulate Treg proliferation. VEGF-A/VEGFR2 blockade reduced Treg proportion and proliferation in tumor-bearing mice and metastatic CRC patients suggesting that combination of anti-VEGF-A/VEGFR2 therapies with immunotherapeutic approaches in the future might be particularly relevant in CRC patients.

Disclosure

J. Taieb: advisory role, Roche; research grant, Roche.

All other authors have declared no conflicts of interest.