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SAR131675, a VEGRF3 Inhibitor, Modulates the Immune Response and Reduces the Growth of Colorectal Cancer Liver

Katrina A Walsh1, Georgios Kastrappis1, Theodora Fifis1

  • 1Department of Surgery, The University of Melbourne, Austin Health, Lance Townsend Building, Level 8, 145 Studley Road, Heidelberg, VIC 3084, Australia.

Cancers
|June 10, 2022
PubMed

Insights

SAR131675, a VEGFR-3 inhibitor, reduced colorectal cancer liver metastases (CLM) and suppressed immunosuppressive myeloid cells in mice. This treatment promoted a more favorable immune environment, potentially aiding tumor growth suppression.

Area of Science:

  • Oncology
  • Immunology
  • Pharmacology

Background:

  • Colorectal cancer (CRC) frequently metastasizes to the liver (CLM), necessitating improved therapeutic strategies.
  • Targeted therapies offer potential for enhanced CLM treatment outcomes.

Purpose of the Study:

  • To evaluate the efficacy of SAR131675, a selective vascular endothelial growth factor receptor 3 (VEGFR-3) tyrosine kinase inhibitor, in suppressing CLM in a preclinical murine model.
  • To investigate the impact of SAR131675 on tumor growth and the tumor microenvironment's immune cell composition.

Main Methods:

  • Colorectal cancer liver metastases (CLM) were induced intrasplenically in mice.
  • Mice received daily treatment with SAR131675.
  • Tumor burden and immune infiltrates in tumor and liver tissues were analyzed using stereology, immunohistochemistry (IHC), and flow cytometry at multiple time points.

Main Results:

  • SAR131675 treatment significantly reduced tumor burden and liver F4/80+ macrophages.
  • Leukocyte infiltration, particularly myeloid cells (including PD-L1+ subsets), was reduced in the liver.
  • T cell populations (CD3+, CD8+ PD1+) increased, enhancing the CD8+:CD4+ T cell ratio, while tumor tissue showed reduced immunosuppressive myeloid cells and increased CD4+ T cells.

Conclusions:

  • SAR131675 effectively suppresses colorectal cancer liver metastases (CLM) in a murine model.
  • The drug modulates the immune microenvironment, reducing immunosuppressive myeloid cells and promoting anti-tumor T cell responses.
  • These immunomodulatory effects suggest SAR131675 holds promise for improving CLM treatment by creating a less immunosuppressive environment.
Keywords:
VEGFR3colorectal cancerimmune systemliver metastaseslymphangiogenesismyeloid derived suppressor cellstyrosine kinase

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