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

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 Ly6gmonocytic 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,more » OVA-specific CD8+ T cells in melanoma cells expressing OVA. Ultimately, 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.« less
Authors:
 [1] ;  [2] ;  [2] ;  [3] ;  [4]
  1. Ecole Polytechnique Federale Lausanne (Switzlerland). Inst. of Bioengineering; Swiss Inst. for Experimental Cancer Research , Lausanne (Switzerland)
  2. Ecole Polytechnique Federale Lausanne (Switzlerland). Inst. of Bioengineering
  3. 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)
  4. 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
Publication Date:
OSTI Identifier:
1261131
Grant/Contract Number:
02114-08-2007; 02696-08-2010; 206653; 31-13576
Type:
Accepted Manuscript
Journal Name:
Cancer Immunology and Immunotherapy
Additional Journal Information:
Journal Volume: 64; Journal Issue: 8; Journal ID: ISSN 0340-7004
Publisher:
Springer
Research Org:
Argonne National Laboratory (ANL), Argonne, IL (United States); Ecole Polytechnique Federale Lausanne (Switzlerland)
Sponsoring Org:
USDOE; European Research Commission (ERC); Swiss Cancer League; Swiss National Science Foundation
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES MDSC depletion; 6-Thioguanine; Cancer; T cell therapy