Pan-integrin inhibitor GLPG-0187 promotes T-cell killing of mismatch repair-deficient colorectal cancer cells by suppression of SMAD/TGF-β signaling.

Colorectal cancer is the third leading cause of cancer-related death and the third most common cause of cancer. As the five-year survival with advanced metastatic colorectal cancer (mCRC) is 14%, new treatment strategies are needed. Immune checkpoint blockade, which takes advantage of an individual's immune system to fight cancer, has an impact in the clinic; however, for CRC, it is only effective and approved for treating mismatch repair (MMR)-deficient cancer. Moreover, long-term outcomes in MMR-deficient mCRC suggest that most patients are not cured and eventually develop therapy resistance. We hypothesized that targeting TGF-β signaling may enhance immune-mediated T-cell killing by MMR-deficient CRC cells. Using GLPG-0187, an inhibitor of multiple integrin receptors and TGF-β, we demonstrate minimal cytotoxicity against MMR-deficient HCT116 or p53null HCT116 human CRC cells. GLPG-0187 promoted significant immune cell killing of the CRC cells by TALL-104 T lymphoblast cells and reduced phosphoSMAD2 in HCT116 p53-null cells either in the absence or presence of exogenous TGF-β. We observed a reduction in CCL20, CXCL5, prolactin, and TRAIL-R3, while GDF-15 was increased in TALL-104 cells treated with a T-cell activating dose of GLPG-0187 (4 µM). Our results suggest that TGF-β signaling inhibition by a general integrin receptor inhibitor may boost T-cell killing of MMR-deficient colorectal cancer cells and suggest that a combination of anti-GDF-15 in combination with TGF-β blockade be further investigated in the treatment of MMR-deficient mCRC. Our results support the development of a novel immune-based therapeutic strategy to treat colorectal cancer by targeting the TGF-β signaling pathway through integrin receptor blockade.