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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Glycoengineered anti-CD39 promotes anticancer responses by depleting suppressive cells and inhibiting angiogenesis in tumor models
Journal of Clinical Investigation, Volume 132, No. 13, Article e157431, Year 2022
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Description
Immunosuppressive cells accumulating in the tumor microenvironment constitute a formidable barrier that interferes with current immunotherapeutic approaches. A unifying feature of these tumor-associated immune and vascular endothelial cells appears to be the elevated expression of ectonucleotidase CD39, which in tandem with ecto-5′-nucleotidase CD73, catalyzes the conversion of extracellular ATP into adenosine. We glycoengineered an afucosylated anti-CD39 IgG2c and tested this reagent in mouse melanoma and colorectal tumor models. We identified major biological effects of this approach on cancer growth, associated with depletion of immunosuppressive cells, mediated through enhanced Fcγ receptor–directed (FcγRdirected), antibody-dependent cellular cytotoxicity (ADCC). Furthermore, regulatory/exhausted T cells lost CD39 expression, as a consequence of antibody-mediated trogocytosis. Most strikingly, tumor-associated macrophages and endothelial cells with high CD39 expression were effectively depleted following antibody treatment, thereby blocking angiogenesis. Tumor site–specific cellular modulation and lack of angiogenesis synergized with chemotherapy and anti–PD-L1 immunotherapy in experimental tumor models. We conclude that depleting suppressive cells and targeting tumor vasculature, through administration of afucosylated anti-CD39 antibody and the activation of ADCC, comprises an improved, purinergic system–modulating strategy for cancer therapy. Copyright: © 2022, Zhang et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
Authors & Co-Authors
Csizmadia, Eva
United States, Boston
Beth Israel Deaconess Medical Center
Gao, Wenda
Unknown Affiliation
Zhao, Haitao
China, Beijing
Chinese Academy of Medical Sciences & Peking Union Medical College
Robson, Simon Christopher
United States, Boston
Beth Israel Deaconess Medical Center
Statistics
Citations: 8
Authors: 4
Affiliations: 2
Identifiers
Doi:
10.1172/JCI157431
ISSN:
00219738
Research Areas
Cancer
Health System And Policy