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

• Ngôn ngữ: eng
• Ký hiệu phân loại: 574.87 [Unassigned]
• Thông tin xuất bản: Brussels, Belgium : Oak Ridge, Tenn. : Belgium. Office of the European Research Council Executive Agency (ERCEA) ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2015
• Mô tả vật lý: Size: p. 1033-1046 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 261157
• Chủ đề: 1. 59 basic biological sciences; 2. 60 applied life sciences; 3. 6-thioguanine; 4. Cancer; 5. Mdsc depletion; 6. T cell therapy

Tóm tắt

 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<
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  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<
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  granulocytic MDSCs (G-MDSCs) in the draining LNs, and Gr1<
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  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<
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  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<
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  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.