title: CXCL12/CXCR4 blockade induces multimodal antitumor effects that prolong survival in an immunocompetent mouse model of ovarian cancer.
abstract: The chemokine CXCL12 and its receptor CXCR4 are expressed widely in human cancers, including ovarian cancer, in which they are associated with disease progression at the levels of tumor cell proliferation, invasion, and angiogenesis. Here, we used an immunocompetent mouse model of intraperitoneal papillary epithelial ovarian cancer to show that modulation of the CXCL12/CXCR4 axis in ovarian cancer has multimodal effects on tumor pathogenesis associated with induction of antitumor immunity. siRNA-mediated knockdown of CXCL12 in BR5-1 cells that constitutively express CXCL12 and CXCR4 reduced cell proliferation in vitro, and tumor growth in vivo. Similarly, treatment of BR5-1-derived tumors with AMD3100, a selective CXCR4 antagonist, resulted in increased tumor apoptosis and necrosis, reduction in intraperitoneal dissemination, and selective reduction of intratumoral FoxP3(+) regulatory T cells (Treg). Compared with controls, CXCR4 blockade greatly increased T-cell-mediated antitumor immune responses, conferring a significant survival advantage to AMD3100-treated mice. In addition, the selective effect of CXCR4 antagonism on intratumoral Tregs was associated with both higher CXCR4 expression and increased chemotactic responses to CXCL12, a finding that was also confirmed in a melanoma model. Together, our findings reinforce the concept of a critical role for the CXCL12/CXCR4 axis in ovarian cancer pathogenesis, and they offer a definitive preclinical validation of CXCR4 as a therapeutic target in this disease.
authors: Vaccine and Immunotherapy Center, Infectious Diseases Medicine, Massachusetts General Hospital, Charlestown, MA.|Department of Experimental Medicine and IST Cancer Research, Genoa University, Italy.
authors: Elda
authors: E
authors: Righi
authors: Vaccine and Immunotherapy Center, Infectious Diseases Medicine, Massachusetts General Hospital, Charlestown, MA.
authors: Satoshi
authors: S
authors: Kashiwagi
authors: Vaccine and Immunotherapy Center, Infectious Diseases Medicine, Massachusetts General Hospital, Charlestown, MA.
authors: Jianping
authors: J
authors: Yuan
authors: Vaccine and Immunotherapy Center, Infectious Diseases Medicine, Massachusetts General Hospital, Charlestown, MA.
authors: Michael
authors: M
authors: Santosuosso
authors: Vaccine and Immunotherapy Center, Infectious Diseases Medicine, Massachusetts General Hospital, Charlestown, MA.
authors: Pierre
authors: P
authors: Leblanc
authors: Vaccine and Immunotherapy Center, Infectious Diseases Medicine, Massachusetts General Hospital, Charlestown, MA.
authors: Rachel
authors: R
authors: Ingraham
authors: Vaccine and Immunotherapy Center, Infectious Diseases Medicine, Massachusetts General Hospital, Charlestown, MA.
authors: Benjamin
authors: B
authors: Forbes
authors: Vaccine and Immunotherapy Center, Infectious Diseases Medicine, Massachusetts General Hospital, Charlestown, MA.
authors: Beth
authors: B
authors: Edelblute
authors: Vaccine and Immunotherapy Center, Infectious Diseases Medicine, Massachusetts General Hospital, Charlestown, MA.
authors: Brian
authors: B
authors: Collette
authors: Molecular Pathology, Massachusetts General Hospital, Boston, MA.
authors: Deyin
authors: D
authors: Xing
authors: Vaccine and Immunotherapy Center, Infectious Diseases Medicine, Massachusetts General Hospital, Charlestown, MA.|Department of Zoology, Clare College, Cambridge, UK.
authors: Magdalena
authors: M
authors: Kowalski
authors: Department of Experimental Medicine and IST Cancer Research, Genoa University, Italy.
authors: Maria Cristina
authors: MC
authors: Mingari
authors: Dept of Haematology, Padua University Hospital, Italy.
authors: Fabrizio
authors: F
authors: Vianello
authors: Gynecological Oncology Cancer Center, Massachusetts General Hospital, Boston, MA.
authors: Michael
authors: M
authors: Birrer
authors: Molecular Pathology, Massachusetts General Hospital, Boston, MA.|Women's Cancer Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
authors: Sandra
authors: S
authors: Orsulic
authors: Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA.
authors: Glenn
authors: G
authors: Dranoff
authors: Vaccine and Immunotherapy Center, Infectious Diseases Medicine, Massachusetts General Hospital, Charlestown, MA.
authors: Mark C
authors: MC
authors: Poznansky
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000235:genetics*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D055785:Gene Knockdown Techniques; D007121:Immunocompetence; D051379:Mice; D010051:Ovarian Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D019718:Receptors, CXCR4 / Q000235:genetics*; D015996:Survival Rate
chemical_list: C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D019718:Receptors, CXCR4