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Role of OGR1 in myeloid-derived cells in prostate cancer
1Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, USA.
Abstract:
Ovarian cancer G-protein-coupled-receptor-1 (OGR1) is a tumor metastasis suppressor in prostate cancer (PCa). OGR1 knockout mice (ogr1(-/-)) are grossly normal under physiological conditions, however, reduced melanoma tumorigenesis has been observed, with the mechanisms of this reduction completely unknown. In this work, we demonstrated that OGR1 deficiency in host cells significantly reduced tumorigenesis of PCa in mice. Adoptive transfer of WT CD11b(+) Gr1(+) double positive (DP) cells, but not T cells, was sufficient to allow tumor development in ogr1(-/-) mice. The expression of an M1 macrophage marker, inducible nitric oxide synthase (iNOS) was higher and expression of an M2 macrophage marker, arginase-1 (Arg 1) was lower in tumors from ogr1(-/-) mice compared with WT mice. Furthermore, coinjection of transgenic adenocarcinoma mouse prostate (TRAMP)-C2 cells with WT, but not ogr1(-/-) macrophages, increased tumor incidence in ogr1(-/-) mice. T-cell depletion experiments suggested that T cells were required for tumor rejection in ogr1(-/-)mice, although OGR1 expression in T cells may not be necessary. In summary, the expression of OGR1 in myeloid-derived cells, especially in DP cells, was required for PCa tumor cell-induced immunosuppression.
Insights
Ovarian cancer G-protein-coupled-receptor-1 (OGR1) deficiency in host myeloid cells, particularly double-positive (DP) cells, suppresses prostate cancer (PCa) growth. OGR1 is crucial for PCa-induced immunosuppression, with its absence promoting T-cell-mediated tumor rejection.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Ovarian cancer G-protein-coupled-receptor-1 (OGR1) acts as a tumor metastasis suppressor in prostate cancer (PCa).
- OGR1 knockout mice exhibit reduced melanoma tumorigenesis, but the underlying mechanisms remain unclear.
Purpose of the Study:
- To investigate the role of OGR1 deficiency in host cells on prostate cancer (PCa) tumorigenesis.
- To elucidate the cellular mechanisms by which OGR1 influences PCa development and immune response.
Main Methods:
- Utilized OGR1 knockout (ogr1(-/-)) mice and wild-type (WT) mice for prostate cancer (PCa) implantation studies.
- Performed adoptive transfer experiments using WT CD11b(+) Gr1(+) double positive (DP) cells and T cells.
- Analyzed macrophage polarization markers (iNOS and Arg 1) in tumors and assessed T-cell involvement via depletion studies.
Main Results:
- OGR1 deficiency in host cells significantly reduced PCa tumorigenesis in mice.
- Adoptive transfer of WT DP cells, but not T cells, restored tumor development in ogr1(-/-) mice.
- OGR1 deficiency promoted an M1 macrophage phenotype (higher iNOS, lower Arg 1) and was required for T-cell-mediated tumor rejection.
Conclusions:
- OGR1 expression in myeloid-derived cells, especially DP cells, is essential for prostate cancer (PCa) tumor cell-induced immunosuppression.
- OGR1 deficiency enhances anti-tumor immunity, leading to reduced PCa growth, potentially through altered macrophage polarization and intact T-cell surveillance.
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