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Cancers (Basel). 2014 Feb 28;6(1):472-90. doi: 10.3390/cancers6010472.

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

Author information

  • 1UMR5273 INSERM U1031/CNRS/EFS StromaLab, Toulouse 31432, France. nicolas.espagnolle@efs.sante.fr.
  • 2Sanofi Recherche et Développement, Early to Candidate DPU, Toulouse 31036, France. pauline.barron@sanofi.com.
  • 3Sanofi Recherche et Développement, Early to Candidate DPU, Toulouse 31036, France. marie.mandron@sanofi.com.
  • 4Sanofi Recherche et Développement, Early to Candidate DPU, Toulouse 31036, France. isabelle.blanc@sanofi.com.
  • 5Sanofi Recherche et Développement, Early to Candidate DPU, Toulouse 31036, France. jacques.bonnin@sanofi.com.
  • 6Molecular Biology Unit, Biologics Department, Sanofi, Vitry-sur-Seine 94400, France. magali.agnel@sanofi.com.
  • 7Molecular Biology Unit, Biologics Department, Sanofi, Vitry-sur-Seine 94400, France. erwan.kerbellec@sanofi.com.
  • 8Sanofi Recherche et Développement, Early to Candidate DPU, Toulouse 31036, France. jean-pascal.herault@sanofi.com.
  • 9Sanofi Recherche et Développement, Early to Candidate DPU, Toulouse 31036, France. pierre.savi@hotmail.fr.
  • 10Sanofi Recherche et Développement, Early to Candidate DPU, Toulouse 31036, France. oise.bono@sanofi.com.
  • 11Sanofi Recherche et Développement, Early to Candidate DPU, Toulouse 31036, France. antoine.alam@sanofi.com.

Abstract

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.

PMID:
24589997
[PubMed]
PMCID:
PMC3980599
Free PMC Article

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