PGE(2)-induced CXCL12 production and CXCR4 expression controls the accumulation of human MDSCs in ovarian cancer environment.

Signals mediated by CXCL12 (SDF1) and its receptor CXCR4 are centrally involved in cancer progression, both directly by activating cancer cells and indirectly by inducing angiogenesis plus recruiting T regulatory and plasmacytoid dendritic immune cells. Here, we show that in ascites isolated from ovarian cancer patients, both CXCL12 and CXCR4 are controlled by the tumor-associated inflammatory mediator prostaglandin E(2) (PGE(2)), which attracts myeloid-derived suppressor cells (MDSC) into the ascites microenvironment. In this setting, PGE(2) was essential both for expression of functional CXCR4 in cancer-associated MDSCs and for production of its ligand CXCL12. Frequencies of CD11b(+)CD14(+)CD33(+)CXCR4(+) MDSCs closely correlated with CXCL12 and PGE(2) levels in patient ascites. MDSCs migrated toward ovarian cancer ascites in a CXCR4-dependent manner that required COX2 activity and autocrine PGE(2) production. Inhibition of COX2 or the PGE(2) receptors EP2/EP4 in MDSCs suppressed expression of CXCR4 and MDSC responsiveness to CXCL12 or ovarian cancer ascites. Similarly, COX2 inhibition also blocked CXCL12 production in the ovarian cancer environment and its ability to attract MDSCs. Together, our findings elucidate a central role for PGE(2) in MDSC accumulation triggered by the CXCL12-CXCR4 pathway, providing a powerful rationale to target PGE(2) signaling in ovarian cancer therapy.

[1]  P. Dahm,et al.  Circulating and tumor‐infiltrating myeloid cell subsets in patients with bladder cancer , 2012, International journal of cancer.

[2]  S. Rosenzweig,et al.  Tumor Secretion of VEGF Induces Endothelial Cells to Suppress T cell Functions Through the Production of PGE2 , 2010, Journal of immunotherapy.

[3]  Srinivas Nagaraj,et al.  Myeloid-derived suppressor cells as regulators of the immune system , 2009, Nature Reviews Immunology.

[4]  D. Bartlett,et al.  Ability of mature dendritic cells to interact with regulatory T cells is imprinted during maturation. , 2008, Cancer research.

[5]  J. Nyström,et al.  Recruitment and activation of natural killer cells in vitro by a human dendritic cell vaccine. , 2008, Cancer research.

[6]  P. Dahm,et al.  Oxidative Stress Regulates Expression of VEGFR1 in Myeloid Cells: Link to Tumor-Induced Immune Suppression in Renal Cell Carcinoma1 , 2008, The Journal of Immunology.

[7]  D. Gabrilovich,et al.  Tumor escape mechanism governed by myeloid-derived suppressor cells. , 2008, Cancer research.

[8]  P. Sinha,et al.  Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. , 2007, Cancer research.

[9]  G. Rabinovich,et al.  Immunosuppressive strategies that are mediated by tumor cells. , 2007, Annual review of immunology.

[10]  W. Zou.  Regulatory T cells, tumour immunity and immunotherapy , 2006, Nature Reviews Immunology.

[11]  Paolo Serafini,et al.  Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression. , 2006, Seminars in cancer biology.

[12]  Dennis C. Sgroi,et al.  Stromal Fibroblasts Present in Invasive Human Breast Carcinomas Promote Tumor Growth and Angiogenesis through Elevated SDF-1/CXCL12 Secretion , 2005, Cell.

[13]  Weiping Zou,et al.  Immunosuppressive networks in the tumour environment and their therapeutic relevance , 2005, Nature Reviews Cancer.

[14]  Lieve Moons,et al.  CXCL12 and vascular endothelial growth factor synergistically induce neoangiogenesis in human ovarian cancers. , 2005, Cancer research.

[15]  D. Gabrilovich.  Mechanisms and functional significance of tumour-induced dendritic-cell defects , 2004, Nature Reviews Immunology.

[16]  Brian Barnett,et al.  Bone Marrow Is a Reservoir for CD4+CD25+ Regulatory T Cells that Traffic through CXCL12/CXCR4 Signals , 2004, Cancer Research.

[17]  W. Isaacs,et al.  Cyclooxygenases in cancer: progress and perspective. , 2004, Cancer letters.

[18]  George Coukos,et al.  Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival , 2004, Nature Medicine.

[19]  F. Balkwill.  Cancer and the chemokine network , 2004, Nature Reviews Cancer.

[20]  M. Burdick,et al.  Cyclooxygenase-2-Dependent Expression of Angiogenic CXC Chemokines ENA-78/CXC Ligand (CXCL) 5 and Interleukin-8/CXCL8 in Human Non-Small Cell Lung Cancer , 2004, Cancer Research.

[21]  R. Salcedo,et al.  Role of Chemokines in Angiogenesis: CXCL12/SDF‐1 and CXCR4 Interaction, a Key Regulator of Endothelial Cell Responses , 2003, Microcirculation.

[22]  M. Huang,et al.  Tumor cyclooxygenase 2-dependent suppression of dendritic cell function. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[23]  T. Hla,et al.  Induction of cyclooxygenase-2 in monocyte/macrophage by mucins secreted from colon cancer cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[24]  Gordon Stamp,et al.  Multiple actions of the chemokine CXCL12 on epithelial tumor cells in human ovarian cancer. , 2002, Cancer research.

[25]  D. Gabrilovich,et al.  Immature myeloid cells and cancer-associated immune suppression , 2002, Cancer Immunology, Immunotherapy.

[26]  T. Curiel,et al.  Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells , 2001, Nature Medicine.

[27]  V. Bronte,et al.  Tumor-induced immune dysfunctions caused by myeloid suppressor cells. , 2001, Journal of immunotherapy.

[28]  T. Mcclanahan,et al.  Involvement of chemokine receptors in breast cancer metastasis , 2001, Nature.

[29]  J. Banchereau,et al.  IL-6 switches the differentiation of monocytes from dendritic cells to macrophages , 2000, Nature Immunology.

[30]  C. Harris,et al.  Human mesothelioma samples overexpress both cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (NOS2): in vitro antiproliferative effects of a COX-2 inhibitor. , 2000, Cancer research.

[31]  Shu-Hsia Chen,et al.  Gr-1+ Myeloid Cells Derived from Tumor-Bearing Mice Inhibit Primary T Cell Activation Induced Through CD3/CD28 Costimulation1 , 2000, The Journal of Immunology.

[32]  J. Blay,et al.  Inhibition of the differentiation of dendritic cells from CD34(+) progenitors by tumor cells: role of interleukin-6 and macrophage colony-stimulating factor. , 1998, Blood.

[33]  D. Carbone,et al.  Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. , 1998, Blood.

[34]  D. Carbone,et al.  Decreased antigen presentation by dendritic cells in patients with breast cancer. , 1997, Clinical cancer research : an official journal of the American Association for Cancer Research.

[35]  P. Alexander.  Prostaglandins and cancer , 1982, Nature.

[36]  加藤 弘.  COX-2 and prostaglandin EP3/EP4 signaling regulate the tumor stromal proangiogenic microenvironment via CXCL12-CXCR4 chemokine systems , 2010 .

[37]  Fumitaka Kikkawa,et al.  Involvement of SDF-1alpha/CXCR4 axis in the enhanced peritoneal metastasis of epithelial ovarian carcinoma. , 2008, International journal of cancer.

[38]  Fumitaka Kikkawa,et al.  Involvement of SDF‐1α/CXCR4 axis in the enhanced peritoneal metastasis of epithelial ovarian carcinoma , 2008 .

[39]  S. Ostrand-Rosenberg,et al.  The terminology issue for myeloid-derived suppressor cells. , 2007, Cancer research.