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

Abstract

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 Ly6chi 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, Ly6clo Ly6g+ granulocytic MDSCs (G-MDSCs) in the draining LNs, and Gr1int Mo-MDSCs in the tumor. In both tumor models, MC-TG decreased the numbers of circulating Mo- and G-MDSCs, as well as of Ly6chi 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00262-015-1702-8) contains supplementary material, which is available to authorized users.

Current understanding of interactions between nanoparticles and the immune system

“…This example offers an effective way to prolong drug function in the tumor environment by using a nanodelivery approach. Other recent examples include using poly (ethyleneimine) nanoparticles for the delivery of antiPD-1 siRNA (Teo et al, 2015), branched polyethyleneimine-superparamagnetic iron oxide nanoparticles for the enhancement of Th1 cell polarization of DCs (Hoang et al, 2015), 6-thioguanine-loaded polymeric micelles for the depletion of MDSCs (Jeanbart et al, 2015), and a CD4-targeted, oil-in-water emulsion for the co-delivery of IL-2 and TGF-β (McHugh et al, 2015). …”

Nanomedicine approaches to improve cancer immunotherapy

“…They found that MC‐TG NPs more effectively decreased the numbers of circulating monocytic and granulocytic MDSCs than equal doses of free TG. Overall, this MDSC‐depleting strategy enhanced cancer immunotherapy in the B16‐F10 melanoma model …”

Nanoengineered Immune Niches for Reprogramming the Immunosuppressive Tumor Microenvironment and Enhancing Cancer Immunotherapy

“…Poly(propylene sulfide)–PEG micelles were developed to encapsulate 6‐thioguanine for the depletion of MDSCs in EG7 and B16 tumor‐bearing mice, and they enhanced the efficacy of adoptive T‐cell therapy . The sub‐30 nm polymeric micelles allowed the efficient delivery of 6‐thioguanine to the lymphatic system to deplete monocytic MDSCs in the TME and spleen and granulocytic MDSCs in the tumor‐draining lymph nodes.…”