skip to main content

DOE PAGESDOE PAGES

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 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 significantlymore » 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.« 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:
Grant/Contract Number:
02114-08-2007; 02696-08-2010; 206653; 31-13576; AC02-06CH11357
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 Lab. (ANL), Argonne, IL (United States); Ecole Polytechnique Federale Lausanne (Switzlerland)
Sponsoring Org:
USDOE; European Research Commission (ERC); Swiss Cancer League; Swiss National Science Foundation (SNSF); USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22). Materials Sciences and Engineering Division
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; MDSC depletion; 6-Thioguanine; Cancer; T cell therapy; 59 BASIC BIOLOGICAL SCIENCES
OSTI Identifier:
1261131
Alternate Identifier(s):
OSTI ID: 1332936

Jeanbart, Laura, Kourtis, Iraklis C., van der Vlies, André J., Swartz, Melody A., and Hubbell, Jeffrey A.. 6-Thioguanine-loaded polymeric micelles deplete myeloid-derived suppressor cells and enhance the efficacy of T cell immunotherapy in tumor-bearing mice. United States: N. p., Web. doi:10.1007/s00262-015-1702-8.
Jeanbart, Laura, Kourtis, Iraklis C., van der Vlies, André J., Swartz, Melody A., & Hubbell, Jeffrey A.. 6-Thioguanine-loaded polymeric micelles deplete myeloid-derived suppressor cells and enhance the efficacy of T cell immunotherapy in tumor-bearing mice. United States. doi:10.1007/s00262-015-1702-8.
Jeanbart, Laura, Kourtis, Iraklis C., van der Vlies, André J., Swartz, Melody A., and Hubbell, Jeffrey A.. 2015. "6-Thioguanine-loaded polymeric micelles deplete myeloid-derived suppressor cells and enhance the efficacy of T cell immunotherapy in tumor-bearing mice". United States. doi:10.1007/s00262-015-1702-8. https://www.osti.gov/servlets/purl/1261131.
@article{osti_1261131,
title = {6-Thioguanine-loaded polymeric micelles deplete myeloid-derived suppressor cells and enhance the efficacy of T cell immunotherapy in tumor-bearing mice},
author = {Jeanbart, Laura and Kourtis, Iraklis C. and van der Vlies, André J. and Swartz, Melody A. and Hubbell, Jeffrey A.},
abstractNote = {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. 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.},
doi = {10.1007/s00262-015-1702-8},
journal = {Cancer Immunology and Immunotherapy},
number = 8,
volume = 64,
place = {United States},
year = {2015},
month = {5}
}