Depleting Immunosuppressive Cells with Tumor Cells to Overcome Acquired Resistance to PD-1 Blockade

Abstract

Antitumor therapies exploiting immune checkpoint blockade (ICB) have been showing promising effects in treating cancer in many clinical cases. However, there are malignant tumor variants that appear resistant to those ICB therapies, and those tumor cells that respond to primary ICB therapies often, gradually, become resistant to them. Our lab discovered a combinational therapy approach that utilized a common antigen marker, CD73, shared by both tumor cells and major types of immunosuppressive cells in the tumor microenvironment (TME), to effectively eradicate advanced tumor. It is critical that depleting all major types of immunosuppressive cells drastically inhibit immune regulations and suppressions which are supportive for tumor burden. In addition, combinational targeting with PD-1 ICB further augmented the overall efficacies of the therapies. Administrating IR700-CD73-antibody-dye conjugates and PD-1 monoclonal antibody with near infrared (NIR) irradiation to the grown solid tumor sites can successfully eradicate tumor to avoid later refractory response. Our study demonstrated that the depleting of both tumor cells and surrounding immunosuppressive cells effectively eradicate tumor by overcoming the acquired resistance of the tumor cells to ICB.