Oncotarget

Research Papers:

Increasing the efficacy of radiotherapy by modulating the CCR2/CCR5 chemokine axes

Kelli A. Connolly, Brian A. Belt, Nathania M. Figueroa, Aditi Murthy, Ankit Patel, Minsoo Kim, Edith M. Lord, David C. Linehan and Scott A. Gerber _

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Oncotarget. 2016; 7:86522-86535. https://doi.org/10.18632/oncotarget.13287

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Abstract

Kelli A. Connolly1, Brian A. Belt2, Nathania M. Figueroa2, Aditi Murthy1, Ankit Patel2, Minsoo Kim1, Edith M. Lord1, David C. Linehan2, Scott A. Gerber1,2

1Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA

2Department of Surgery, University of Rochester Medical Center, Rochester, NY 14642, USA

Correspondence to:

Scott A. Gerber, email: [email protected]

Keywords: radiotherapy, myeloid cells, chemokines, immunotherapy, immune response

Received: August 02, 2016     Accepted: October 29, 2016     Published: November 11, 2016

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.


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