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 04:00:00 UTC 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 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. 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.

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

Sponsoring Organization:: USDOE; European Research Commission (ERC); Swiss Cancer League; Swiss National Science Foundation

OSTI ID:: 1261131

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

Publisher:: SpringerCopyright Statement

Country of Publication:: United States

Language:: English

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Peripherally Administered Nanoparticles Target Monocytic Myeloid Cells, Secondary Lymphoid Organs and Tumors in Mice Kourtis, Iraklis C.; Hirosue, Sachiko; de Titta, Alexandre PLoS ONE, Vol. 8, Issue 4 https://doi.org/10.1371/journal.pone.0061646	journal	April 2013
Clinical Perspectives on Targeting of Myeloid Derived Suppressor Cells in the Treatment of Cancer Najjar, Yana G.; Finke, James H. Frontiers in Oncology, Vol. 3 https://doi.org/10.3389/fonc.2013.00049	journal	January 2013
Intratumoral Injection of CpG Oligonucleotides Induces the Differentiation and Reduces the Immunosuppressive Activity of Myeloid-Derived Suppressor Cells Shirota, Yuko; Shirota, Hidekazu; Klinman, Dennis M. The Journal of Immunology, Vol. 188, Issue 4 https://doi.org/10.4049/jimmunol.1101304	journal	January 2012
Blockade of Myeloid-Derived Suppressor Cells after Induction of Lymphopenia Improves Adoptive T Cell Therapy in a Murine Model of Melanoma Kodumudi, Krithika N.; Weber, Amy; Sarnaik, Amod A. The Journal of Immunology, Vol. 189, Issue 11 https://doi.org/10.4049/jimmunol.1200274	journal	October 2012
Reciprocal Relationship between Myeloid-Derived Suppressor Cells and T Cells Nagaraj, Srinivas; Youn, Je-In; Gabrilovich, Dmitry I. The Journal of Immunology, Vol. 191, Issue 1 https://doi.org/10.4049/jimmunol.1300654	journal	June 2013
Tumor-Induced CD11b ⁺ Gr-1 ⁺ Myeloid Cells Suppress T Cell Sensitization in Tumor-Draining Lymph Nodes Watanabe, Satoshi; Deguchi, Katsuya; Zheng, Rongxiu The Journal of Immunology, Vol. 181, Issue 5 https://doi.org/10.4049/jimmunol.181.5.3291	journal	August 2008
Subsets of Myeloid-Derived Suppressor Cells in Tumor-Bearing Mice Youn, Je-In; Nagaraj, Srinivas; Collazo, Michelle The Journal of Immunology, Vol. 181, Issue 8 https://doi.org/10.4049/jimmunol.181.8.5791	journal	October 2008

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