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