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Stimulating TAM-mediated anti-tumor immunity with mannose-decorated nanoparticles in ovarian cancer

BACKGROUND: Current cancer immunotherapies have made tremendous impacts but generally lack high response rates, especially in ovarian cancer. New therapies are needed to provide increased benefits. One understudied approach is to target the large population of immunosuppressive tumor-associated macr...

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Autores principales: Glass, Evan B., Hoover, Alyssa A., Bullock, Kennady K., Madden, Matthew Z., Reinfeld, Bradley I., Harris, Whitney, Parker, Dominique, Hufnagel, Demetra H., Crispens, Marta A., Khabele, Dineo, Rathmell, W. Kimryn, Rathmell, Jeffrey C., Wilson, Andrew J., Giorgio, Todd D., Yull, Fiona E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9074180/
https://www.ncbi.nlm.nih.gov/pubmed/35513776
http://dx.doi.org/10.1186/s12885-022-09612-2
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author Glass, Evan B.
Hoover, Alyssa A.
Bullock, Kennady K.
Madden, Matthew Z.
Reinfeld, Bradley I.
Harris, Whitney
Parker, Dominique
Hufnagel, Demetra H.
Crispens, Marta A.
Khabele, Dineo
Rathmell, W. Kimryn
Rathmell, Jeffrey C.
Wilson, Andrew J.
Giorgio, Todd D.
Yull, Fiona E.
author_facet Glass, Evan B.
Hoover, Alyssa A.
Bullock, Kennady K.
Madden, Matthew Z.
Reinfeld, Bradley I.
Harris, Whitney
Parker, Dominique
Hufnagel, Demetra H.
Crispens, Marta A.
Khabele, Dineo
Rathmell, W. Kimryn
Rathmell, Jeffrey C.
Wilson, Andrew J.
Giorgio, Todd D.
Yull, Fiona E.
author_sort Glass, Evan B.
collection PubMed
description BACKGROUND: Current cancer immunotherapies have made tremendous impacts but generally lack high response rates, especially in ovarian cancer. New therapies are needed to provide increased benefits. One understudied approach is to target the large population of immunosuppressive tumor-associated macrophages (TAMs). Using inducible transgenic mice, we recently reported that upregulating nuclear factor-kappaB (NF-κB) signaling in TAMs promotes the M1, anti-tumor phenotype and limits ovarian cancer progression. We also developed a mannose-decorated polymeric nanoparticle system (MnNPs) to preferentially deliver siRNA payloads to M2, pro-tumor macrophages in vitro. In this study, we tested a translational strategy to repolarize ovarian TAMs via MnNPs loaded with siRNA targeting the inhibitor of NF-κB alpha (IκBα) using mouse models of ovarian cancer. METHODS: We evaluated treatment with MnNPs loaded with IκBα siRNA (IκBα-MnNPs) or scrambled siRNA in syngeneic ovarian cancer models. ID8 tumors in C57Bl/6 mice were used to evaluate consecutive-day treatment of late-stage disease while TBR5 tumors in FVB mice were used to evaluate repetitive treatments in a faster-developing disease model. MnNPs were evaluated for biodistribution and therapeutic efficacy in both models. RESULTS: Stimulation of NF-κB activity and repolarization to an M1 phenotype via IκBα-MnNP treatment was confirmed using cultured luciferase-reporter macrophages. Delivery of MnNPs with fluorescent payloads (Cy5-MnNPs) to macrophages in the solid tumors and ascites was confirmed in both tumor models. A three consecutive-day treatment of IκBα-MnNPs in the ID8 model validated a shift towards M1 macrophage polarization in vivo. A clear therapeutic effect was observed with biweekly treatments over 2-3 weeks in the TBR5 model where significantly reduced tumor burden was accompanied by changes in immune cell composition, indicative of reduced immunosuppressive tumor microenvironment. No evidence of toxicity associated with MnNP treatment was observed in either model. CONCLUSIONS: In mouse models of ovarian cancer, MnNPs were preferentially associated with macrophages in ascites fluid and solid tumors. Evidence of macrophage repolarization, increased inflammatory cues, and reduced tumor burden in IκBα-MnNP-treated mice indicate beneficial outcomes in models of established disease. We have provided evidence of a targeted, TAM-directed approach to increase anti-tumor immunity in ovarian cancer with strong translational potential for future clinical studies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-022-09612-2.
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spelling pubmed-90741802022-05-07 Stimulating TAM-mediated anti-tumor immunity with mannose-decorated nanoparticles in ovarian cancer Glass, Evan B. Hoover, Alyssa A. Bullock, Kennady K. Madden, Matthew Z. Reinfeld, Bradley I. Harris, Whitney Parker, Dominique Hufnagel, Demetra H. Crispens, Marta A. Khabele, Dineo Rathmell, W. Kimryn Rathmell, Jeffrey C. Wilson, Andrew J. Giorgio, Todd D. Yull, Fiona E. BMC Cancer Research BACKGROUND: Current cancer immunotherapies have made tremendous impacts but generally lack high response rates, especially in ovarian cancer. New therapies are needed to provide increased benefits. One understudied approach is to target the large population of immunosuppressive tumor-associated macrophages (TAMs). Using inducible transgenic mice, we recently reported that upregulating nuclear factor-kappaB (NF-κB) signaling in TAMs promotes the M1, anti-tumor phenotype and limits ovarian cancer progression. We also developed a mannose-decorated polymeric nanoparticle system (MnNPs) to preferentially deliver siRNA payloads to M2, pro-tumor macrophages in vitro. In this study, we tested a translational strategy to repolarize ovarian TAMs via MnNPs loaded with siRNA targeting the inhibitor of NF-κB alpha (IκBα) using mouse models of ovarian cancer. METHODS: We evaluated treatment with MnNPs loaded with IκBα siRNA (IκBα-MnNPs) or scrambled siRNA in syngeneic ovarian cancer models. ID8 tumors in C57Bl/6 mice were used to evaluate consecutive-day treatment of late-stage disease while TBR5 tumors in FVB mice were used to evaluate repetitive treatments in a faster-developing disease model. MnNPs were evaluated for biodistribution and therapeutic efficacy in both models. RESULTS: Stimulation of NF-κB activity and repolarization to an M1 phenotype via IκBα-MnNP treatment was confirmed using cultured luciferase-reporter macrophages. Delivery of MnNPs with fluorescent payloads (Cy5-MnNPs) to macrophages in the solid tumors and ascites was confirmed in both tumor models. A three consecutive-day treatment of IκBα-MnNPs in the ID8 model validated a shift towards M1 macrophage polarization in vivo. A clear therapeutic effect was observed with biweekly treatments over 2-3 weeks in the TBR5 model where significantly reduced tumor burden was accompanied by changes in immune cell composition, indicative of reduced immunosuppressive tumor microenvironment. No evidence of toxicity associated with MnNP treatment was observed in either model. CONCLUSIONS: In mouse models of ovarian cancer, MnNPs were preferentially associated with macrophages in ascites fluid and solid tumors. Evidence of macrophage repolarization, increased inflammatory cues, and reduced tumor burden in IκBα-MnNP-treated mice indicate beneficial outcomes in models of established disease. We have provided evidence of a targeted, TAM-directed approach to increase anti-tumor immunity in ovarian cancer with strong translational potential for future clinical studies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-022-09612-2. BioMed Central 2022-05-06 /pmc/articles/PMC9074180/ /pubmed/35513776 http://dx.doi.org/10.1186/s12885-022-09612-2 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Glass, Evan B.
Hoover, Alyssa A.
Bullock, Kennady K.
Madden, Matthew Z.
Reinfeld, Bradley I.
Harris, Whitney
Parker, Dominique
Hufnagel, Demetra H.
Crispens, Marta A.
Khabele, Dineo
Rathmell, W. Kimryn
Rathmell, Jeffrey C.
Wilson, Andrew J.
Giorgio, Todd D.
Yull, Fiona E.
Stimulating TAM-mediated anti-tumor immunity with mannose-decorated nanoparticles in ovarian cancer
title Stimulating TAM-mediated anti-tumor immunity with mannose-decorated nanoparticles in ovarian cancer
title_full Stimulating TAM-mediated anti-tumor immunity with mannose-decorated nanoparticles in ovarian cancer
title_fullStr Stimulating TAM-mediated anti-tumor immunity with mannose-decorated nanoparticles in ovarian cancer
title_full_unstemmed Stimulating TAM-mediated anti-tumor immunity with mannose-decorated nanoparticles in ovarian cancer
title_short Stimulating TAM-mediated anti-tumor immunity with mannose-decorated nanoparticles in ovarian cancer
title_sort stimulating tam-mediated anti-tumor immunity with mannose-decorated nanoparticles in ovarian cancer
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9074180/
https://www.ncbi.nlm.nih.gov/pubmed/35513776
http://dx.doi.org/10.1186/s12885-022-09612-2
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