1. 6-Thioguanine-loaded polymeric micelles deplete myeloid-derived suppressor cells and enhance the efficacy of T cell immunotherapy in tumor-bearing mice
- Author
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Iraklis Kourtis, Melody A. Swartz, Jeffrey A. Hubbell, Laura Jeanbart, and André J. van der Vlies
- Subjects
Cancer Research ,Thymoma ,Polymers ,medicine.medical_treatment ,T cell ,Immunology ,Melanoma, Experimental ,Apoptosis ,Mice, Transgenic ,Spleen ,CD8-Positive T-Lymphocytes ,Immunotherapy, Adoptive ,Mice ,Tumor Microenvironment ,medicine ,Animals ,Humans ,Immunology and Allergy ,Myeloid Cells ,Thioguanine ,Micelles ,Cancer ,Tumor microenvironment ,business.industry ,Melanoma ,6-Thioguanine ,Immunotherapy ,medicine.disease ,Mice, Inbred C57BL ,Leukemia ,medicine.anatomical_structure ,Oncology ,T cell therapy ,Myeloid-derived Suppressor Cell ,Female ,Immunization ,Original Article ,business ,CD8 ,MDSC depletion - 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 material The online version of this article (doi:10.1007/s00262-015-1702-8) contains supplementary material, which is available to authorized users.
- Published
- 2015