title: Increasing the efficacy of radiotherapy by modulating the CCR2/CCR5 chemokine axes.
abstract: Although radiotherapy (RT) is widely used to control tumor growth across many cancer types, there is a relatively high incidence of RT failure exhibited by tumor recurrence, therefore a clear need exists to achieve improved effectiveness of RT. The RT-elicited immune response largely impacts the efficacy of RT and includes immune cells that kill tumor cells, but also immunosuppressive cells, which dampen anti-tumor immunity. Using murine models in which syngeneic tumor cell lines (Colon38, Glioma261, Line1) are grown intramuscularly and treated with 15 Gy local RT, we assessed the effects of RT on both the systemic and intratumoral immune response. Here we demonstrate that RT stimulates increased production of two chemokines, CCL2 and CCL5, at the tumor site. Further, that this leads to increased CCR2+ CCR5+ monocytes in circulation and subsequently alters the intratumoral immune infiltrate favoring the largely immunosuppressive CCR2+ CCR5+ monocytes. Importantly, a CCR2/CCR5 antagonist administered daily (15 mg/kg subcutaneously) starting two days prior to RT reduces both circulating and intratumoral monocytes resulting in increased efficacy of RT in radioresponsive tumors. Overall, these data have important implications for the mechanism of RT and present a means to improve RT efficacy across many cancer types.
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Kelli A
authors.initials: KA
authors.lastname: Connolly
authors.affiliation: Department of Surgery, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Belt
authors.affiliation: Department of Surgery, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Nathania M
authors.initials: NM
authors.lastname: Figueroa
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Aditi
authors.initials: A
authors.lastname: Murthy
authors.affiliation: Department of Surgery, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Ankit
authors.initials: A
authors.lastname: Patel
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Minsoo
authors.initials: M
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Edith M
authors.initials: EM
authors.lastname: Lord
authors.affiliation: Department of Surgery, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Linehan
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA.|Department of Surgery, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Gerber
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology; D009374:Neoplasms, Experimental / Q000276:immunology / Q000532:radiotherapy*; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D019713:Receptors, CCR5 / Q000502:physiology*
chemical_list: D054390:Receptors, CCR2; D019713:Receptors, CCR5
keywords: chemokines; immune response; immunotherapy; myeloid cells; radiotherapy