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

Cancer Immunology, Immunotherapy, Aug 2015

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.

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

6Thioguanineloaded polymeric micelles deplete myeloidderived suppressor cells and enhance the efficacy of T cell immunotherapy in tumorbearing mice Laura Jeanbart 1 2 3 Iraklis C. Kourtis 1 2 3 Andr J. van der Vlies 1 2 3 Melody A. Swartz 0 1 2 3 4 Jeffrey A. Hubbell 0 1 2 3 4 0 Institute for Chemical Sciences and Engineering, School of Basic Sciences, EPFL , Lausanne , Switzerland 1 Materials Science Division, Argonne National Laboratory , Argonne, IL , USA 2 Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, EPFL , Lausanne , Switzerland 3 Institute of Bioengineering, School of Life Sciences and School of Engineering, Ecole Polytechnique Federale de Lausanne (EPFL) , Lausanne , Switzerland 4 Institute for Molecular Engineering, University of Chicago , Chicago, IL , USA 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, T cell therapy - 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. 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. MDSC depletion 6-Thioguanine Cancer Bone marrow Dendritic cell Granulocytic Over the past decades, many novel cancer immunotherapies have been developed to boost anti-tumor immunity, targeting a variety of mechanisms including tumor antigen presentation by dendritic cells (DCs), anti-tumor T cell priming, overall T cell activation status, immune suppression, and T cell infiltration in the tumor [1, 2]. Strategies have included cell-based therapies such as transfer of ex vivo activated DCs or engineered T cells as well as antibody-based therapies that target specific T cell inhibitory pathways including CTLA-4 or PD-1/PD-L1 [36]. Despite these efforts, many therapeutic modalities encounter limited success because of tumor-induced immune suppression and evasion mechanisms [69]. It has been shown that targeting these immune suppressive mechanisms can lead to enhanced immunotherapy efficacy in cancer [1014]. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells, characterized by their expression of CD11b and Gr1 and lack of MHCII; they comprise a Ly6chi Ly6g Gr1int monocytic subset (Mo-MDSCs) and a Ly6clo Ly6g+ Gr1hi granulocytic subset (G-MDSCs) [15]. MDSCs are induced by tumor-mediated inflammation [1618], recruited to the circulation via tumor-derived factors such as IL-1, IL-6, GM-CSF, G-CSF, and VEGF [1921], and accumulate in the tumor, tumor-draining lymph node (LN), and spleen, with MDSC numbers increasing with tumor load [16, 21]. MDSCs play a major role in anti-tumor immunity by inhibiting both CD8+ and CD4+ T cell activation, proliferation, and homing [16, 17, 22, 23]. G-MDSCs infiltrate and exert their suppressive activity in an antigen-specific manner in the LNs, while Mo-MDSCs, considered as the more suppressive ones, infiltrate and suppress T cell responses in the spleen and tumor [18, 2426]. 1 3 Strategies to target MDSCs, and thereby improve local T cell function, include depletion (affecting both recruitment and expansion in the tumor), functional inhibition, and differentiation into mature antigen-presenting cells [27, 28]. Ly6chi monocytes and Mo-MDSCs traffic from the bone marrow (BM) to sites of inflammation via CCR2-signaling [29], and therapeutic strategies based on CCR2-siRNA showed significant reduction in inflammatory monocyte effects in murine models of atherosclerosis, cancer, and diabetes [30]. Also, all-trans-retinoic acid (RA), which is important for hematopoietic (...truncated)


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Laura Jeanbart, Iraklis C. Kourtis. 6-Thioguanine-loaded polymeric micelles deplete myeloid-derived suppressor cells and enhance the efficacy of T cell immunotherapy in tumor-bearing mice, Cancer Immunology, Immunotherapy, 2015, pp. 1033-1046, Volume 64, Issue 8, DOI: 10.1007/s00262-015-1702-8