PILOT: Plk1 in the Efficacy of Immune Therapy

Background: Myeloid-derived suppressor cells (MDSCs) represent one of the key barriers to the success of adoptive immunotherapy by suppressing T cells. Eliminating MDSCs can improve response rates to cancer therapy and patient survival. Various preclinical studies and clinical trials targeting MDSC showed promising results. So far, however, there are no FDA approved drugs developed to target MDSCs. Polo-like kinase 1 (PLK1) is a serine/threonine-protein kinase, whose overexpression is oncogenic and is associated with poor prognosis in various cancers, therefore PLK1 is considered as an attractive cancer target. The Plk1 inhibitor volasertib has shown considerable promise in clinical studies, and was awarded breakthrough drug status. However, the possible impact of this agent on suppressive MDSCs remains elusive. Our preliminary data showed that volasertib depleted tumor-induced MDSCs, thereby averting one major mechanism of cancer-mediated immunosuppression. Moreover, the activation of CD8+ T cells were restored in volasertib-treated mice. We therefore reasoned that volasertib may create a favorable environment that may allow for successful combinatory immunotherapy. The objective of the proposed study is to determine whether PLK1-targeted therapy can synergize with PD1 pathway blockade to enhance antitumor immunity. Because the development of the antitumor immune response is associated with the accumulation and activation of tumorinfiltrating CD8+ T cells in the tumor milieu and MDSCs are known to suppress CD8+ T cells activity. Therefore, reduction of MDSCs amounts and suppressive functions will increase CD8+ T cells frequencies and restore their functions in vivo. Based on this, we hypothesis that Plk1 inhibition will enhance the efficacy of immune therapy. Our hypothesis will be tested by pursuing two Specific Aims - (1) to examine whether volasertib impedes the suppressive activity of residual MDSC; and (2) to examine whether volasertib enhances the efficacy of immune checkpoint inhibitors. Study Design: These complementary aims will be accomplished by using flow cytometry analyses and employing both cell culture systems and xenograft models. This contribution is significant in cancer therapies because, if positive, the results of the proposed study will support an immediate clinical trial to compare the efficacy of volaparib, immune checkpoint inhibitors, and the combination of volaparib with anti-PD-1 in patients.