Modulating the Tumor Microenvironment to Improve Immunotherapy Treatments

Advances in immunotherapy are revolutionizing the treatments of certain cancers, especially those in the blood. However, wider applications for eradicating solid tumors have been slow to emerge. A likely reason is the presence of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment that secrete immunosuppressive molecules which attenuate the attack of immune cells. We hypothesize that small molecule Wnt/Beta- Catenin inhibitors can be used to modulate the immunosuppressive actions of MDSCs and increase the effectiveness of immunotherapy treatments, such as with chimeric antigen receptor (CAR) T-cells. The Wnt/Beta-Catenin Pathway has been shown to be a crucial driving force behind the immunosuppressive effects exerted by various cells within the tumor microenvironment (TME), including MDSCs, regulatory T-cells, and cancer cells. Our project goal is to test if inhibitors of the Wnt/Beta-Catenin Pathway can increase the infiltration, proliferation, and effectiveness of anticancer immune cells in the TME. To date, we have developed a workflow for identifying lead compounds that alter the immunosuppressive actions of MDSCs without toxicity to human T-cells. Peripheral Blood Mononuclear Cells (PBMCs) are isolated from healthy human donors and differentiated into MDSCs using pro-inflammatory cytokines commonly found within the TME. Fluorescence Activated Cell Sorting (FACS) and antibody-based magnetic cell sorting are used to prepare and validate human MDSCs for use in assays. Compounds are tested for toxicity against donor T-cells to determine non-toxic concentrations for future assays and filter for MDSC specific compounds. This workflow is now poised to identify novel compounds that modulate the immunosuppressive actions of MDSCs via Wnt/Beta- Catenin inhibition. This work is part of an ongoing collaboration with the laboratories of Dr. Steven Katz at the Roger Williams Medical Center and Dr. Jyothi Menon at the University of Rhode Island