| Summary: | Most patients with colorectal cancer (CRC) develop metastases, predominantly in the liver (CLM). Targeted therapies are being investigated to improve current CLM treatments. This study tested the effectiveness of SAR131675, a selective VEGFR-3 tyrosine kinase inhibitor, to inhibit CLM in a murine model. Following intrasplenic induction of CLM, mice were treated daily with SAR131675. Tumor growth and immune infiltrates into tumor and liver tissues were assessed at 10-, 16- and 22-days post tumor induction by stereology, IHC and flow cytometry. SAR151675 treatment significantly reduced tumor burden and F4/80<sup>+</sup> macrophages in the liver tissues. Analysis of immune cell infiltrates in liver showed tissue that at day 22, had the proportion of CD45<sup>+</sup> leukocytes significantly reduced, particularly myeloid cells. Analysis of myeloid cells (CD11b<sup>+</sup> CD45<sup>+</sup>) indicated that the proportion of F4/80<sup>−</sup> Ly6C<sup>low</sup> was significantly reduced, including a predominate PD-L1<sup>+</sup> subset, while CD3<sup>+</sup> T cells increased, particularly CD8<sup>+</sup> PD1<sup>+</sup>, reflected by an increase in the CD8<sup>+</sup>:CD4<sup>+</sup> T cell ratio. In the tumor tissue SAR11675 treatment reduced the predominant population of F4/80<sup>+</sup> Ly6C<sup>lo</sup> and increased CD4<sup>+</sup> T cells. These results suggest that SAR131675 alters the immune composition within tumor and the surrounding liver in the later stages of development, resulting in a less immunosuppressive environment. This immunomodulation effect may contribute to the suppression of tumor growth.
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