Effects of in vitro ATRA treatment on human MDSC expansion and function.

Abstract

125 Background: Myeloid derived suppressor cells (MDSCs) are a heterogeneous population of immature immunosuppressive myeloid cells that are expanded in tumor bearing hosts. Melanoma patients with high frequencies of MDSCs have decreased overall survival and an increased risk of death and disease progression, as well as impaired responses to ipilimumab. Targeting MDSCs to decease their frequency or suppressive activity may provide an effective means to improve the efficacy of anti-cancer therapies. All-trans retinoic acid (ATRA) is a vitamin A derivative currently used to treat APL that may target MDSCs. ATRA differentiates immature myeloid cells into macrophages, dendritic cells, or granulocytes. ATRA has been tested as an MDSC targeting agent in two completed caner clinical trials and is being investigated in several other open and completed trials. Methods: We purified myeloid cells from LRS chambers collected from normal donors. The purified cells were treated with GM-CSF+IL-6, GM-CSF+IL-4, or melanoma conditioned media with or without ATRA. After 5 days of incubation, PCR was used to determine the expression of immunoregulatory genes. Additionally, we used a MLR to determine the effect of ATRA on MDSC’s T cell suppressive function. Results: Here we report that in vitro ATRA treatment decreases the expression of ARG1, NOX1, INOS, and PD-L1. Further, we report that ATRA treatment improved T cell proliferation. Conclusions: Controlling MDSC suppressive function and accumulation may provide a mechanism to improve the efficacy of many current cancer therapies. Here we show that ATRA reduces the expression of the immunosuppressive genes ARG1, NOX1, INOS, and PD-L1 in MDSCs. Additionally, we show that treatment of MDSCs with ATRA decreases MDSC’s ability to suppress T cell proliferation. These results indicate that ATRA may improve the efficacy of conventional and immnunotherapeutic treatments.