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

Jeanbart, Laura; Kourtis, Iraklis C.; van der Vlies, André J.; Swartz, Melody A.; Hubbell, Jeffrey A.

doi:10.1007/s00262-015-1702-8

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

Journal Article · Sat May 16 00:00:00 EDT 2015 · Cancer Immunology and Immunotherapy

DOI:https://doi.org/10.1007/s00262-015-1702-8· OSTI ID:1261131

Jeanbart, Laura ^[1]; Kourtis, Iraklis C. ^[2]; van der Vlies, André J. ^[2]; Swartz, Melody A. ^[3]; Hubbell, Jeffrey A. ^[4]

Ecole Polytechnique Federale Lausanne (Switzlerland). Inst. of Bioengineering; Swiss Inst. for Experimental Cancer Research , Lausanne (Switzerland)
Ecole Polytechnique Federale Lausanne (Switzlerland). Inst. of Bioengineering
Ecole Polytechnique Federale Lausanne (Switzlerland). Inst. of Bioengineering; Swiss Inst. for Experimental Cancer Research , Lausanne (Switzerland); Ecole Polytechnique Federale Lausanne (Switzlerland). Inst. for Chemical Sciences and Engineering; Univ. of Chicago, IL (United States)
Ecole Polytechnique Federale Lausanne (Switzlerland). Inst. of Bioengineering; Ecole Polytechnique Federale Lausanne (Switzlerland). Inst. for Chemical Sciences and Engineering; Univ. of Chicago, IL (United States); Argonne National Lab. (ANL), Argonne, IL (United States). Materials Science Division

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 MDSCdepleting 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. As a result, 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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States); Ecole Polytechnique Federale Lausanne (EPFL) (Switzerland)

Sponsoring Organization:: European Research Commission (ERC); Swiss Cancer League; Swiss National Science Foundation (SNSF); USDOE Office of Science (SC), Basic Energy Sciences (BES). Materials Sciences and Engineering Division

Grant/Contract Number:: 02114-08-2007; 02696-08-2010; 206653; 31-13576; AC02-06CH11357

OSTI ID:: 1261131

Alternate ID(s):: OSTI ID: 1332936

Journal Information:: Cancer Immunology and Immunotherapy, Vol. 64, Issue 8; ISSN 0340-7004

Publisher:: SpringerCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 53 works

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60 APPLIED LIFE SCIENCES
MDSC depletion
6-Thioguanine
Cancer
T cell therapy
59 BASIC BIOLOGICAL SCIENCES

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

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