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

Abstract

BackgroundMyeloid 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.MethodsCB-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.ResultsCB-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.ConclusionsThese 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.

FcγR interaction is not required for effective anti‐PD‐L1 immunotherapy but can add additional benefit depending on the tumor model

“…We observed that this enhanced antitumor efficacy correlated with the reduction of a tumor‐infiltrated myeloid subset in CT26 tumor. For this tumor model, an association between an elevated number of myeloid cells and the increased magnitude of their immunosuppressive tumor microenvironment was reported while elimination of these cells can lead to strong antitumor responses . Preferential reduction of this myeloid subset by anti‐PD‐L1 mIgG2a may be due to its high levels of surface PD‐L1 expression compared to other immune and nonimmune cells, similar to that proposed for anti‐CTLA4 mAb, which preferentially depletes high CTLA4 expressing regulatory T cells .…”

Role of l‐arginine and CD11b+Gr‐1+ cells in immunosuppression induced by Heligmosomoides polygyrus bakeri

“…As this cell population was not the focus of our study, we cannot exclude that l ‐arginine metabolism modifications affected these cells as well. Nonetheless, inhibition of arginase activity was shown to alter the immunity . Therefore, altered Gr‐1+ activity related to arginase inhibition during infection can result in reduced immunosuppression and/or activation of protective mechanisms that effected in lower count of the nematodes collected from the intestines.…”

Macrophage targeting: opening new possibilities for cancer immunotherapy

“…It is also reported that TAM isolated from the subcutaneous tumours established by C3 fibrosarcoma or LLC cells express high levels of ARG1 and suppress T‐cell proliferation via ARG1‐mediated mechanisms . In mice that have received orthotopic injection of 4T1 mammary tumour cells, the treatment with anti‐PD1/anti‐CTLA4 antibodies combined with an ARG1 inhibitor (CB‐1158) significantly suppresses primary tumour growth and lung metastases . Likewise, treatment with CB‐1158 enhances the tumour suppressive effect of anti‐PD‐L1 antibody in mice with subcutaneous tumours developed by CT26 colon cancer cells .…”

“…48,49 In mice that have received orthotopic injection of 4T1 mammary tumour cells, the treatment with anti-PD1/anti-CTLA4 antibodies combined with an ARG1 inhibitor (CB-1158) significantly suppresses primary tumour growth and lung metastases. 50 Likewise, treatment with CB-1158 enhances the tumour suppressive effect of anti-PD-L1 antibody in mice with subcutaneous tumours developed by CT26 colon cancer cells. 45 These results highlight the possibility that molecular targeting of TAM-derived factors can be another approach to prevent TAM-mediated restriction of checkpoint therapy (Fig.…”