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

Abstract

Simple SummaryColorectal cancer most often metastasizes to the liver, and in most cases, it is unresectable at diagnosis. New treatment options targeting specific cancer characteristics are needed and are currently being explored. Herein we looked at the use of a selective VEGFR-3 tyrosine kinase inhibitor, SAR131675, as an anti-tumor agent in a mouse model of colorectal liver metastasis. We found that SAR131675 dramatically reduced tumor growth and changed the immune response within the tumor and the surrounding liver, suggesting the use of SAR131675 as an adjuvant therapy for colorectal liver metastasis.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+ macrophages in the liver tissues. Analysis of immune cell infiltrates in liver showed tissue that at day 22, had the proportion of CD45+ leukocytes significantly reduced, particularly myeloid cells. Analysis of myeloid cells (CD11b+ CD45+) indicated that the proportion of F4/80− Ly6Clow was significantly reduced, including a predominate PD-L1+ subset, while CD3+ T cells increased, particularly CD8+ PD1+, reflected by an increase in the CD8+:CD4+ T cell ratio. In the tumor tissue SAR11675 treatment reduced the predominant population of F4/80+ Ly6Clo and increased CD4+ 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.