Targeting Tumor-Induced Immunosuppression Using Conventional Cancer Therapeutics

Abstract

Immunosuppression remains a challenge in the immunotherapy field and needs to be combated to increase survival of patients suffering from cancer. There have been no phase III trials that have in an organized, statistically reliable setting compared immunotherapy outcome with or without so called preconditioning, or metronomic conditioning, in randomized settings. The current view on preconditioning is that it may be used both to reduce tumor load and to reduce suppressive immune cells prior to immunotherapy. For combination treatments, immunotherapy such as checkpoint blockade has shown benefit in combination with chemotherapy even if the major goals of those studies may not have been to condition the patient for a better immune response due to reduced immunosuppression. Nevertheless, there is a need to further enhance the promising effect of cancer immunotherapy. We argue herein that there are several interesting conventional cancer therapeutics to explore for combinational use with immunotherapy to enhance response rates and achieve a longer overall survival of patients. This review will discuss mechanisms of conventional cancer therapeutics of interest for combination therapy. For example, gemcitabine and several tyrosine kinase inhibitors have profound effect on myeloid-derived suppressor cells while tyrosine kinase inhibitors can enhance T cell infiltration into tumors likely due to increased chemokine signaling. Further, cyclophosphamide is well known for its capacity to reduce Tregs and is used to precondition patients prior T cell therapy. How to combine these agents with immunotherapy to further increase patient survival is an important next step in the immunotherapeutic field.