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Cancers 2014, 6(1), 472-490;

Specific Inhibition of the VEGFR-3 Tyrosine Kinase by SAR131675 Reduces Peripheral and Tumor Associated Immunosuppressive Myeloid Cells

UMR5273 INSERM U1031/CNRS/EFS StromaLab, Toulouse 31432, France
Sanofi Recherche et Développement, Early to Candidate DPU, Toulouse 31036, France
Molecular Biology Unit, Biologics Department, Sanofi, Vitry-sur-Seine 94400, France
Author to whom correspondence should be addressed.
Received: 18 November 2013 / Revised: 6 February 2014 / Accepted: 17 February 2014 / Published: 28 February 2014
(This article belongs to the Special Issue Tumor Associated Macrophages)
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Myeloid derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) represent prominent components in cancer progression. We previously showed that inhibition of the VEGFR-3 pathway by SAR131675 leads to reduction of TAM infiltration and tumor growth. Here, we found that treatment with SAR131675 prevents the accumulation of immunosuppressive blood and splenic MDSCs which express VEGFR-3, in 4T1 tumor bearing mice. Moreover we showed that soluble factors secreted by tumor cells promote MDSCs proliferation and differentiation into M2 polarized F4/80+ macrophages. In addition, cell sorting and transcriptomic analysis of tumor infiltrating myeloid cells revealed the presence of a heterogeneous population that could be divided into 3 subpopulations: (i) immature cells with a MDSC phenotype (GR1+/CD11b+/F4/80); (ii) “immuno-incompetent” macrophages (F4/80high/CD86neg/MHCIILow) strongly expressing M2 markers such as Legumain, CD206 and Mgl1/2 and (iii) “immuno-competent”-M1 like macrophages (F4/80Low/CD86+/MHCIIHigh). SAR131675 treatment reduced MDSCs in lymphoid organs as well as F4/80High populations in tumors. Interestingly, in the tumor SAR131675 was able to increase the immunocompetent M1 like population (F4/80low). Altogether these results demonstrate that the specific VEGFR-3 inhibitor SAR131675 exerts its anti tumoral activity by acting on different players that orchestrate immunosuppression and cancer progression in a tumoral context: MDSCs in peripheral lymphoid organs and TAMs infiltrating the tumor. View Full-Text
Keywords: VEGFR-3; macrophages; MDSCs; angiogenesis; lymphangiogenesis VEGFR-3; macrophages; MDSCs; angiogenesis; lymphangiogenesis

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Espagnolle, N.; Barron, P.; Mandron, M.; Blanc, I.; Bonnin, J.; Agnel, M.; Kerbelec, E.; Herault, J.P.; Savi, P.; Bono, F.; Alam, A. Specific Inhibition of the VEGFR-3 Tyrosine Kinase by SAR131675 Reduces Peripheral and Tumor Associated Immunosuppressive Myeloid Cells. Cancers 2014, 6, 472-490.

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