A novel microtubule inhibitor modulates the myeloid PD-L1 expression, restores T cell effector function, and promotes apoptosis for effective suppression of colorectal cancer.

The rising incidence of colorectal cancer (CRC) in recent decades has ranked it as the third most common cause of cancer-related mortality worldwide. The goal in this study was to determine the mechanism(s) by which VERU-111 alters the immune landscape in the tumor microenvironment to facilitate suppression of CRC. We found that VERU-111 halted wound healing in human colorectal carcinoma cell lines HCT-116 and DLD-1, caused cell cycle arrest, and disrupted microtubule assembly in vitro. We found that oral administration of VERU-111 reduced tumor burden and increased colon length relative to controls in the azoxymethane (AOM) and dextran sodium sulfate (DSS)-induced murine model of CRC. We observed an increase in the number and frequency of CXCR3-expressing CD8-activated T cells and natural killer T (NKT) cells in the colon tumor microenvironment (CTM) in mice treated with VERU-111 as compared to vehicle control. VERU-111 increased the expression of NKG2D activating receptors and production of interferon-gamma (IFN-γ) ex vivo in mouse spleen-derived NK cells. Intriguingly, VERU-111 treatment reduced the frequency of macrophages and dendritic cells (DCs) expressing the programmed cell death ligand 1 (PD-L1) in the CTM and increased the frequency of macrophages, relative to controls. We also observed the induction of apoptosis by upregulation of the apoptotic markers BAX and cleaved caspase-3 (CC3), and TUNEL-positive apoptotic hotspots in tumors of mice treated with VERU-111. These findings suggest that VERU-111 effectively reduces tumor burden and suppresses CRC by recruiting effector T cells, NK cells, inducing apoptosis, and reducing myeloid cells expressing PD-L1 in CTM.