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J Immunother Cancer. 2017 Dec 19;5(1):101. doi: 10.1186/s40425-017-0308-4.

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

Author information

1
Calithera Biosciences, 343 Oyster Point Boulevard, Suite 200, South San Francisco, CA, 94080, USA. ssteggerda@calithera.com.
2
Calithera Biosciences, 343 Oyster Point Boulevard, Suite 200, South San Francisco, CA, 94080, USA.
3
Max Planck Institute for Biochemistry, Martinsried, Germany.
4
Departments of Infectious Diseases and Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

KEYWORDS:

Arg1; Arg2; Arginase; Arginine; Checkpoint blockade; Granulocyte; Immunotherapy; Myeloid derived suppressor cell; Tumor associated macrophage; Tumor microenvironment

PMID:
29254508
PMCID:
PMC5735564
DOI:
10.1186/s40425-017-0308-4
[Indexed for MEDLINE]
Free PMC Article

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