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Novel phosphatidylserine-binding molecule enhances antitumor T-cell responses by targeting immunosuppressive exosomes in human tumor microenvironments

BACKGROUND: The human tumor microenvironment (TME) is a complex and dynamic milieu of diverse acellular and cellular components, creating an immunosuppressive environment, which contributes to tumor progression. We have previously shown that phosphatidylserine (PS) expressed on the surface of exosom...

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Autores principales: Bhatta, Maulasri, Shenoy, Gautam N, Loyall, Jenni L, Gray, Brian D, Bapardekar, Meghana, Conway, Alexis, Minderman, Hans, Kelleher Jr, Raymond J, Carreno, Beatriz M, Linette, Gerald, Shultz, Leonard D, Odunsi, Kunle, Balu-Iyer, Sathy V, Pak, Koon Yan, Bankert, Richard B
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488709/
https://www.ncbi.nlm.nih.gov/pubmed/34599030
http://dx.doi.org/10.1136/jitc-2021-003148
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author Bhatta, Maulasri
Shenoy, Gautam N
Loyall, Jenni L
Gray, Brian D
Bapardekar, Meghana
Conway, Alexis
Minderman, Hans
Kelleher Jr, Raymond J
Carreno, Beatriz M
Linette, Gerald
Shultz, Leonard D
Odunsi, Kunle
Balu-Iyer, Sathy V
Pak, Koon Yan
Bankert, Richard B
author_facet Bhatta, Maulasri
Shenoy, Gautam N
Loyall, Jenni L
Gray, Brian D
Bapardekar, Meghana
Conway, Alexis
Minderman, Hans
Kelleher Jr, Raymond J
Carreno, Beatriz M
Linette, Gerald
Shultz, Leonard D
Odunsi, Kunle
Balu-Iyer, Sathy V
Pak, Koon Yan
Bankert, Richard B
author_sort Bhatta, Maulasri
collection PubMed
description BACKGROUND: The human tumor microenvironment (TME) is a complex and dynamic milieu of diverse acellular and cellular components, creating an immunosuppressive environment, which contributes to tumor progression. We have previously shown that phosphatidylserine (PS) expressed on the surface of exosomes isolated from human TMEs is causally linked to T-cell immunosuppression, representing a potential immunotherapeutic target. In this study, we investigated the effect of ExoBlock, a novel PS-binding molecule, on T-cell responses in the TME. METHODS: We designed and synthesized a new compound, (ZnDPA)(6)-DP-15K, a multivalent PS binder named ExoBlock. The PS-binding avidity of ExoBlock was tested using an in vitro competition assay. The ability of this molecule to reverse exosome-mediated immunosuppression in vitro was tested using human T-cell activation assays. The in vivo therapeutic efficacy of ExoBlock was then tested in two different human tumor xenograft models, the melanoma-based xenomimetic (X-)mouse model, and the ovarian tumor-based omental tumor xenograft (OTX) model. RESULTS: ExoBlock was able to bind PS with high avidity and was found to consistently and significantly block the immunosuppressive activity of human ovarian tumor and melanoma-associated exosomes in vitro. ExoBlock was also able to significantly enhance T cell-mediated tumor suppression in vivo in both the X-mouse and the OTX model. In the X-mouse model, ExoBlock suppressed tumor recurrence in a T cell-dependent manner. In the OTX model, ExoBlock treatment resulted in an increase in the number as well as function of CD4 and CD8 T cells in the TME, which was associated with a reduction in tumor burden and metastasis, as well as in the number of circulating PS+ exosomes in tumor-bearing mice. CONCLUSION: Our results establish that targeting exosomal PS in TMEs with ExoBlock represents a promising strategy to enhance antitumor T-cell responses.
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spelling pubmed-84887092021-10-14 Novel phosphatidylserine-binding molecule enhances antitumor T-cell responses by targeting immunosuppressive exosomes in human tumor microenvironments Bhatta, Maulasri Shenoy, Gautam N Loyall, Jenni L Gray, Brian D Bapardekar, Meghana Conway, Alexis Minderman, Hans Kelleher Jr, Raymond J Carreno, Beatriz M Linette, Gerald Shultz, Leonard D Odunsi, Kunle Balu-Iyer, Sathy V Pak, Koon Yan Bankert, Richard B J Immunother Cancer Oncolytic and Local Immunotherapy BACKGROUND: The human tumor microenvironment (TME) is a complex and dynamic milieu of diverse acellular and cellular components, creating an immunosuppressive environment, which contributes to tumor progression. We have previously shown that phosphatidylserine (PS) expressed on the surface of exosomes isolated from human TMEs is causally linked to T-cell immunosuppression, representing a potential immunotherapeutic target. In this study, we investigated the effect of ExoBlock, a novel PS-binding molecule, on T-cell responses in the TME. METHODS: We designed and synthesized a new compound, (ZnDPA)(6)-DP-15K, a multivalent PS binder named ExoBlock. The PS-binding avidity of ExoBlock was tested using an in vitro competition assay. The ability of this molecule to reverse exosome-mediated immunosuppression in vitro was tested using human T-cell activation assays. The in vivo therapeutic efficacy of ExoBlock was then tested in two different human tumor xenograft models, the melanoma-based xenomimetic (X-)mouse model, and the ovarian tumor-based omental tumor xenograft (OTX) model. RESULTS: ExoBlock was able to bind PS with high avidity and was found to consistently and significantly block the immunosuppressive activity of human ovarian tumor and melanoma-associated exosomes in vitro. ExoBlock was also able to significantly enhance T cell-mediated tumor suppression in vivo in both the X-mouse and the OTX model. In the X-mouse model, ExoBlock suppressed tumor recurrence in a T cell-dependent manner. In the OTX model, ExoBlock treatment resulted in an increase in the number as well as function of CD4 and CD8 T cells in the TME, which was associated with a reduction in tumor burden and metastasis, as well as in the number of circulating PS+ exosomes in tumor-bearing mice. CONCLUSION: Our results establish that targeting exosomal PS in TMEs with ExoBlock represents a promising strategy to enhance antitumor T-cell responses. BMJ Publishing Group 2021-10-01 /pmc/articles/PMC8488709/ /pubmed/34599030 http://dx.doi.org/10.1136/jitc-2021-003148 Text en © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Oncolytic and Local Immunotherapy
Bhatta, Maulasri
Shenoy, Gautam N
Loyall, Jenni L
Gray, Brian D
Bapardekar, Meghana
Conway, Alexis
Minderman, Hans
Kelleher Jr, Raymond J
Carreno, Beatriz M
Linette, Gerald
Shultz, Leonard D
Odunsi, Kunle
Balu-Iyer, Sathy V
Pak, Koon Yan
Bankert, Richard B
Novel phosphatidylserine-binding molecule enhances antitumor T-cell responses by targeting immunosuppressive exosomes in human tumor microenvironments
title Novel phosphatidylserine-binding molecule enhances antitumor T-cell responses by targeting immunosuppressive exosomes in human tumor microenvironments
title_full Novel phosphatidylserine-binding molecule enhances antitumor T-cell responses by targeting immunosuppressive exosomes in human tumor microenvironments
title_fullStr Novel phosphatidylserine-binding molecule enhances antitumor T-cell responses by targeting immunosuppressive exosomes in human tumor microenvironments
title_full_unstemmed Novel phosphatidylserine-binding molecule enhances antitumor T-cell responses by targeting immunosuppressive exosomes in human tumor microenvironments
title_short Novel phosphatidylserine-binding molecule enhances antitumor T-cell responses by targeting immunosuppressive exosomes in human tumor microenvironments
title_sort novel phosphatidylserine-binding molecule enhances antitumor t-cell responses by targeting immunosuppressive exosomes in human tumor microenvironments
topic Oncolytic and Local Immunotherapy
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488709/
https://www.ncbi.nlm.nih.gov/pubmed/34599030
http://dx.doi.org/10.1136/jitc-2021-003148
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