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Radiation-Induced CXCL16 Release by Breast Cancer Cells Attracts Effector T Cells¹

Satoko Matsumura^*, Baomei Wang^2,*, Noriko Kawashima^*, Steve Braunstein, Michelle Badura, Thomas O. Cameron^*,¶, James S. Babb, Robert J. Schneider, Silvia C. Formenti, Michael L. Dustin^*,¶ and Sandra Demaria^3,*

^* Department of Pathology, Department of Microbiology, Department of Radiology, and Department of Radiation Oncology, New York University School of Medicine, New York, and ^¶ Program in Molecular Pathogenesis, Helen L. and Martin S. Kimmel Center for Biology and Medicine, Skirball Institute for Biomolecular Medicine, New York, NY 10016

Recruitment of effector T cells to inflamed peripheral tissues is regulated by chemokines and their receptors, but the factors regulating recruitment to tumors remain largely undefined. Ionizing radiation (IR) therapy is a common treatment modality for breast and other cancers. Used as a cytocidal agent for proliferating cancer cells, IR in combination with immunotherapy has been shown to promote immune-mediated tumor destruction in preclinical studies. In this study we demonstrate that IR markedly enhanced the secretion by mouse and human breast cancer cells of CXCL16, a chemokine that binds to CXCR6 on Th1 and activated CD8 effector T cells, and plays an important role in their recruitment to sites of inflammation. Using a poorly immunogenic mouse model of breast cancer, we found that irradiation increased the migration of CD8⁺CXCR6⁺ activated T cells to tumors in vitro and in vivo. CXCR6-deficient mice showed reduced infiltration of tumors by activated CD8 T cells and impaired tumor regression following treatment with local IR to the tumor and Abs blocking the negative regulator of T cell activation, CTLA-4. These results provide the first evidence that IR can induce the secretion by cancer cells of proinflammatory chemotactic factors that recruit antitumor effector T cells. The ability of IR to convert tumors into "inflamed" peripheral tissues could be exploited to overcome obstacles at the effector phase of the antitumor immune response and improve the therapeutic efficacy of immunotherapy.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant R01 CA113851, Research Scholar Award RSG-05-145-01-LIB from the American Cancer Society, and a grant from The Chemotherapy Foundation, (to S.D.). Additional support was provided by National Institutes of Health Grant R01AI55037 (to M.L.D.) and a Cancer Research Institute postdoctoral fellowship (to T.O.C.). The New York University Cancer Institute is supported by National Institutes of Health Grant 5P30 CA016087-27.

² Current address: Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8118, St. Louis, MO 63110.

³ Address correspondence and reprint requests to Dr. Sandra Demaria, Department of Pathology, Medical Science Building, Room 504, New York University School of Medicine, 550 First Avenue, New York, NY 10016. E-mail address: demars01{at}med.nyu.edu

⁴ Abbreviations used in this paper: IT, immunotherapy; HA, hemagglutinin; IR, ionizing radiation; MPase, metalloproteinase; NS, nonsilencing; sh, short hairpin; Tc1, T cytotoxic 1; TDLN, tumor-draining lymph node; TIL, tumor infiltrating lymphocyte; WT, wild type.

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