6-Thioguanine-loaded polymeric micelles deplete myeloid-derived suppressor cells and enhance the efficacy of T cell immunotherapy in tumor-bearing mice

摘要: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid that suppress effector T cell responses and can reduce the efficacy cancer immunotherapies. We previously showed ultra-small polymer nanoparticles efficiently drain to lymphatics after intradermal injection target antigen-presenting cells, including Ly6c(hi) Ly6g(-) monocytic MDSCs (Mo-MDSCs), in skin-draining lymph nodes (LNs) spleen. Here, we developed micelles loaded with 6-thioguanine (MC-TG), cytotoxic drug used treatment myelogenous leukemia, aim killing Mo-MDSCs tumor-bearing mice thus enhancing cell-mediated anti-tumor responses. found 2 days post-injection (B16-F10 melanoma or E.G7-OVA thymoma), MC-TG depleted spleen, Ly6c(lo) Ly6g(+) granulocytic (G-MDSCs) draining LNs, Gr1(int) tumor. In both tumor models, decreased numbers circulating Mo- G-MDSCs, as well macrophages, for up 7 following single administration. MDSC depletion was dose dependent more effective than equal doses free TG. Finally, tested whether this MDSC-depleting strategy might enhance immunotherapies B16-F10 model. significantly improved adoptively transferred, OVA-specific CD8(+) expressing OVA. These findings highlight capacity depleting microenvironment show promise promoting immunity when combination