CXCL12/CXCR4 blockade induces multimodal antitumor effects that prolong survival in an immunocompetent mouse model of ovarian cancer

Elda Righi, Satoshi Kashiwagi, Jianping Yuan, Michael Santosuosso, Pierre Leblanc, Rachel Ingraham, Benjamin Forbes, Beth Edelblute, Brian Collette, Deyin Xing, Magdalena Kowalski, Maria Cristina Mingari, Fabrizio Vianello, Michael Birrer, Sandra Orsulic, Glenn Dranoff, Mark C. Poznansky

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)5522-5534
Number of pages13
JournalCancer Research
Volume71
Issue number16
DOIs
Publication statusPublished - Aug 15 2011

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Ovarian Neoplasms
Survival
Neoplasms
Cell Proliferation
CXCR4 Receptors
Chemokine CXCL12
Regulatory T-Lymphocytes
Small Interfering RNA
Disease Progression
Immunity
Melanoma
Necrosis
Apoptosis
T-Lymphocytes
Growth
JM 3100

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Righi, E., Kashiwagi, S., Yuan, J., Santosuosso, M., Leblanc, P., Ingraham, R., ... Poznansky, M. C. (2011). CXCL12/CXCR4 blockade induces multimodal antitumor effects that prolong survival in an immunocompetent mouse model of ovarian cancer. Cancer Research, 71(16), 5522-5534. https://doi.org/10.1158/0008-5472.CAN-10-3143

CXCL12/CXCR4 blockade induces multimodal antitumor effects that prolong survival in an immunocompetent mouse model of ovarian cancer. / Righi, Elda; Kashiwagi, Satoshi; Yuan, Jianping; Santosuosso, Michael; Leblanc, Pierre; Ingraham, Rachel; Forbes, Benjamin; Edelblute, Beth; Collette, Brian; Xing, Deyin; Kowalski, Magdalena; Mingari, Maria Cristina; Vianello, Fabrizio; Birrer, Michael; Orsulic, Sandra; Dranoff, Glenn; Poznansky, Mark C.

In: Cancer Research, Vol. 71, No. 16, 15.08.2011, p. 5522-5534.

Research output: Contribution to journalArticle

Righi, E, Kashiwagi, S, Yuan, J, Santosuosso, M, Leblanc, P, Ingraham, R, Forbes, B, Edelblute, B, Collette, B, Xing, D, Kowalski, M, Mingari, MC, Vianello, F, Birrer, M, Orsulic, S, Dranoff, G & Poznansky, MC 2011, 'CXCL12/CXCR4 blockade induces multimodal antitumor effects that prolong survival in an immunocompetent mouse model of ovarian cancer', Cancer Research, vol. 71, no. 16, pp. 5522-5534. https://doi.org/10.1158/0008-5472.CAN-10-3143
Righi, Elda ; Kashiwagi, Satoshi ; Yuan, Jianping ; Santosuosso, Michael ; Leblanc, Pierre ; Ingraham, Rachel ; Forbes, Benjamin ; Edelblute, Beth ; Collette, Brian ; Xing, Deyin ; Kowalski, Magdalena ; Mingari, Maria Cristina ; Vianello, Fabrizio ; Birrer, Michael ; Orsulic, Sandra ; Dranoff, Glenn ; Poznansky, Mark C. / CXCL12/CXCR4 blockade induces multimodal antitumor effects that prolong survival in an immunocompetent mouse model of ovarian cancer. In: Cancer Research. 2011 ; Vol. 71, No. 16. pp. 5522-5534.
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