Anti-Programmed Cell Death-1 Antibody and Dasatinib Combination Therapy Exhibits Efficacy in Metastatic Colorectal Cancer Mouse Models

SIMPLE SUMMARY: Cancer-associated fibroblasts (CAFs) are abundant in colorectal cancer (CRC) tissues and are essential for tumor growth. Histological analysis of CRC clinical specimens showed that the number of CAFs in liver metastases correlated with the number of CAFs in primary tumors. We hypothesized that the presence of CAFs in metastatic CRC contributes to immune evasion, and thus evaluated the efficacy of dasatinib in targeting CAFs in combination with immunotherapy in a mouse model of liver metastasis. Immunotherapy in combination with dasatinib was shown to reduce stromal components and subsequent immune cell infiltration and promote the activation of tumor immunity and tumor regression in liver metastatic tumors with abundant CAF components. These results suggest that CAFs play an important role in the immune evasion of CRC and that dasatinib is a promising combination agent for increasing immunotherapy sensitivity in metastatic CRC. ABSTRACT: In this study, we investigated the in vivo metastasis suppression effects of the platelet-derived growth factor receptor inhibitor dasatinib, which targets cancer-associated fibroblasts (CAFs), in combination with an anti-programmed cell death-1 (PD-1) antibody. We classified clinical CRC cases as inflamed, excluded, or desert using immunohistochemical analysis and evaluated the tumor stroma. The excluded type was the most common, and cases with high-volume stroma in the primary lesions also had a high stromal volume in the liver metastatic lesions. Liver-metastasis mouse models with different stromal volumes were established and treatment-induced changes in the tumor immune microenvironment were evaluated. The anti-PD-1 antibody alone exhibited a therapeutic effect for the liver metastases with low stromal volumes but not for the liver metastases with high stromal volumes. In contrast, antitumor effects were observed with anti-PD-1 antibody/dasatinib combination therapy even in the liver metastases with high stromal volumes. Combination therapy reduced the stromal volume, promoted immune cell infiltration, induced antitumor cytotoxic T-cell responses, activated antitumor immunity, and promoted tumor regression. These results suggest that CAFs play an important role in the immune evasion of CRC and that anti-PD-1 antibody/dasatinib combination therapy has potential as a treatment option for patients with metastatic CRC for whom immunotherapy alone is ineffective.