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Bhatta M, Shenoy GN, Loyall JL, et al. Novel phosphatidylserine-binding molecule enhances antitumor T-cell responses by targeting immunosuppressive exosomes in human tumor microenvironments. J Immunother Cancer. 2021;9(10)doi: 10.1136/jitc-2021-003148.
Bhatta, M., Shenoy, G. N., Loyall, J. L., Gray, B. D., Bapardekar, M., Conway, A., Minderman, H., Kelleher, R. J., Carreno, B. M., Linette, G., Shultz, L. D., Odunsi, K., Balu-Iyer, S. V., Pak, K. Y., & Bankert, R. B. (2021). Novel phosphatidylserine-binding molecule enhances antitumor T-cell responses by targeting immunosuppressive exosomes in human tumor microenvironments. Journal for immunotherapy of cancer, 9(10), . https://doi.org/10.1136/jitc-2021-003148
Bhatta, Maulasri, et al. "Novel phosphatidylserine-binding molecule enhances antitumor T-cell responses by targeting immunosuppressive exosomes in human tumor microenvironments." Journal for immunotherapy of cancer vol. 9,10 (2021). doi: https://doi.org/10.1136/jitc-2021-003148
Bhatta M, Shenoy GN, Loyall JL, Gray BD, Bapardekar M, Conway A, Minderman H, Kelleher RJ, Carreno BM, Linette G, Shultz LD, Odunsi K, Balu-Iyer SV, Pak KY, Bankert RB. Novel phosphatidylserine-binding molecule enhances antitumor T-cell responses by targeting immunosuppressive exosomes in human tumor microenvironments. J Immunother Cancer. 2021 Oct;9(10). doi: 10.1136/jitc-2021-003148. PMID: 34599030; PMCID: PMC8488709.
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J Immunother Cancer. 2021 Oct;9(10). doi: 10.1136/jitc-2021-003148.

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

Journal for immunotherapy of cancer

Maulasri Bhatta, Gautam N Shenoy, Jenni L Loyall, Brian D Gray, Meghana Bapardekar, Alexis Conway, Hans Minderman, Raymond J Kelleher, Beatriz M Carreno, Gerald Linette, Leonard D Shultz, Kunle Odunsi, Sathy V Balu-Iyer, Koon Yan Pak, Richard B Bankert

Affiliations

  1. Immune Modulatory Therapies LLC, Eden, New York, USA.
  2. Department of Microbiology and Immunology, University at Buffalo, Buffalo, New York, USA.
  3. Molecular Targeting Technologies Inc, West Chester, Pennsylvania, USA.
  4. Flow & Image Cytometry Shared Resource, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.
  5. Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
  6. Jackson Laboratory, Bar Harbor, Maine, USA.
  7. University of Chicago Biological Sciences Division, Chicago, Illinois, USA.
  8. Department of Pharmaceutical Sciences, University at Buffalo-The State University of New York, Buffalo, New York, USA.
  9. Department of Microbiology and Immunology, University at Buffalo, Buffalo, New York, USA [email protected].

PMID: 34599030 PMCID: PMC8488709 DOI: 10.1136/jitc-2021-003148

Abstract

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)

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.

© 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.

Keywords: T-lymphocytes; drug evaluation; immunotherapy; melanoma; preclinical; tumor microenvironment

Conflict of interest statement

Competing interests: The corresponding author, RB, is an officer and founder of Immune Modulatory Therapies LLC. A patent is currently pending for ExoBlock.

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