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Inhibition of arginase by CB-1158 blocks myeloid cell-mediated immune suppression in the tumor microenvironment

Overview of attention for article published in Journal for Immunotherapy of Cancer, December 2017
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  • In the top 5% of all research outputs scored by Altmetric
  • High Attention Score compared to outputs of the same age (93rd percentile)
  • High Attention Score compared to outputs of the same age and source (81st percentile)

Mentioned by

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1 news outlet
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31 X users
patent
3 patents

Citations

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305 Dimensions

Readers on

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218 Mendeley
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Title
Inhibition of arginase by CB-1158 blocks myeloid cell-mediated immune suppression in the tumor microenvironment
Published in
Journal for Immunotherapy of Cancer, December 2017
DOI 10.1186/s40425-017-0308-4
Pubmed ID
Authors

Susanne M. Steggerda, Mark K. Bennett, Jason Chen, Ethan Emberley, Tony Huang, Julie R. Janes, Weiqun Li, Andrew L. MacKinnon, Amani Makkouk, Gisele Marguier, Peter J. Murray, Silinda Neou, Alison Pan, Francesco Parlati, Mirna L. M. Rodriguez, Lee-Ann Van de Velde, Tracy Wang, Melissa Works, Jing Zhang, Winter Zhang, Matthew I. Gross

Abstract

Myeloid cells are an abundant leukocyte in many types of tumors and contribute to immune evasion. Expression of the enzyme arginase 1 (Arg1) is a defining feature of immunosuppressive myeloid cells and leads to depletion of L-arginine, a nutrient required for T cell and natural killer (NK) cell proliferation. Here we use CB-1158, a potent and orally-bioavailable small-molecule inhibitor of arginase, to investigate the role of Arg1 in regulating anti-tumor immunity. CB-1158 was tested for the ability to block myeloid cell-mediated inhibition of T cell proliferation in vitro, and for tumor growth inhibition in syngeneic mouse models of cancer as a single agent and in combination with other therapies. Tumors from animals treated with CB-1158 were profiled for changes in immune cell subsets, expression of immune-related genes, and cytokines. Human tumor tissue microarrays were probed for Arg1 expression by immunohistochemistry and immunofluorescence. Cancer patient plasma samples were assessed for Arg1 protein and L-arginine by ELISA and mass spectrometry, respectively. CB-1158 blocked myeloid cell-mediated suppression of T cell proliferation in vitro and reduced tumor growth in multiple mouse models of cancer, as a single agent and in combination with checkpoint blockade, adoptive T cell therapy, adoptive NK cell therapy, and the chemotherapy agent gemcitabine. Profiling of the tumor microenvironment revealed that CB-1158 increased tumor-infiltrating CD8+ T cells and NK cells, inflammatory cytokines, and expression of interferon-inducible genes. Patient tumor samples from multiple histologies expressed an abundance of tumor-infiltrating Arg1+ myeloid cells. Plasma samples from cancer patients exhibited elevated Arg1 and reduced L-arginine compared to healthy volunteers. These results demonstrate that Arg1 is a key mediator of immune suppression and that inhibiting Arg1 with CB-1158 shifts the immune landscape toward a pro-inflammatory environment, blunting myeloid cell-mediated immune evasion and reducing tumor growth. Furthermore, our results suggest that arginase blockade by CB-1158 may be an effective therapy in multiple types of cancer and combining CB-1158 with standard-of-care chemotherapy or other immunotherapies may yield improved clinical responses.

X Demographics

X Demographics

The data shown below were collected from the profiles of 31 X users who shared this research output. Click here to find out more about how the information was compiled.
Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 218 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 218 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 36 17%
Researcher 34 16%
Student > Bachelor 27 12%
Student > Master 26 12%
Other 7 3%
Other 28 13%
Unknown 60 28%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 43 20%
Agricultural and Biological Sciences 27 12%
Immunology and Microbiology 25 11%
Medicine and Dentistry 18 8%
Pharmacology, Toxicology and Pharmaceutical Science 12 6%
Other 24 11%
Unknown 69 32%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 33. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 10 August 2023.
All research outputs
#1,208,428
of 25,513,063 outputs
Outputs from Journal for Immunotherapy of Cancer
#286
of 3,451 outputs
Outputs of similar age
#27,203
of 447,830 outputs
Outputs of similar age from Journal for Immunotherapy of Cancer
#7
of 32 outputs
Altmetric has tracked 25,513,063 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 95th percentile: it's in the top 5% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 3,451 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 15.7. This one has done particularly well, scoring higher than 91% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 447,830 tracked outputs that were published within six weeks on either side of this one in any source. This one has done particularly well, scoring higher than 93% of its contemporaries.
We're also able to compare this research output to 32 others from the same source and published within six weeks on either side of this one. This one has done well, scoring higher than 81% of its contemporaries.