Promoting antitumor immunity and increased T-cell function by depletion and blockade of the immunosuppressive cell compartment in murine cancer

Abstract

Abstract Tumor growth occurs due to a failure of the immune system to recognize and destroy malignant cells. The cause of breakdown in immune surveillance is at the systemic level and at in the tumor microenvironment. These changes can even occur in the tumor cells themselves to make them less detectable by anticancer immune cells such as downregulation of tumor-associated antigens or decreased expression of antigen presenting molecules such as MHCI. In addition, many cancer types will upregulate immune checkpoint molecules, such as PD-L1 which binds to PD-1 on cytotoxic T-cells to suppress antitumor immune cell function. Immune surveillance can also be curtailed by the presence of immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs) and T-regulatory cells (T-regs) which both serve to dampen antitumor immunity. Our lab utilizes a metronomic low-dose therapeutic approach to examine the effects of anticancer drugs against murine breast cancer and the effects on the immunosuppressive cell compartments. Recent data has shown a reduction in T-regs following treatment with cyclophosphamide, a common chemotherapy. We have also shown that guadecitabine, a second-generation DNA methyl-transferase inhibitor, depletes MDSCs. Here we show that combining low-dose metronomic treatments of guadecitabine and cyclophosphamide leads to a depletion in splenic and tumor MDSCs and T-regs, increased CD8+ T-cell function in the tumor, as well as a reduction in tumor size in FoxP3 reporter mice bearing triple-negative 4T1 tumors. In addition, preliminary studies suggest this antitumor effect is amplified by combining guadecitabine and cyclophosphamide with checkpoint inhibitors such as anti-PD-1, in vivo.