Like Treg cells, myeloid-derived suppressor cells (MDSCs) are suppressive cells found in the tumor microenvironment. MDSCs are a mixed population of immature myeloid cells derived from bone marrow precursors that normally differentiate into monocytes, neutrophils and dendritic cells. However, in pathological conditions such as chronic viral infection, inflammation, and cancer, the development of blood cells results in MDSCs with remarkable immunosuppressive and tumor-promoting activities accumulating in the tumor microenvironment. In several cancer types such as breast cancer and colorectal cancers, the increased accumulation of these cells can be an indication of disease severity and is a poor prognostic factor for patients. Furthermore, the presence of these cells can negatively impact the effectiveness of chemotherapies and possibly immunotherapies such as anti-PD1 checkpoint inhibitors.
Therapeutic targeting of MDSCs represents a promising way to boost antitumor immunity. In mouse models of cancer, blocking the accumulation of MDSCs results in reduced tumor burden. Proposed mechanisms to modulate tumor-associated MDSCs in patients include blocking recruitment or specific depletion of these cells in the tumor microenvironment.
MDSCs within the tumor create a nutrient-poor environment that supports tumor growth and starves T cells that would mount an immune response against the tumor. GCN2 is a stress response kinase that senses starvation within its environment and represses protein translation to help the cell adapt to the nutrient shortage. By inhibiting GCN2, we demonstrated that we can overcome the starvation-induced T cell suppression. In addition, we are exploring additional opportunities to intervene in the MDSC pathway including selective inhibition of one or more suppressive mechanisms, including blockade of inhibitory ligands and cytokines. We believe that targeting MDSCs may also result in considerable therapeutic benefit for cancer patients.
At FLX Bio, we believe strategies to block these suppressive cell types alone and in combination with other immunotherapies will provide considerable benefit to patients and ultimately result in effective immune control and eradication of tumors in cancer patients.