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