The Efficacy of Radiotherapy Relies upon Induction of Type I Interferon–Dependent Innate and Adaptive Immunity

TLDR

Radiotherapy’s antitumor efficacy has been attributed to direct DNA damage, but recent studies show it also enhances T‑cell priming and tumor regression, though the underlying mechanism remains unclear. This study investigates the essential role of type I interferon in mediating local radiotherapy‑induced tumor control. Adenoviral delivery of IFN‑β into tumors, in the absence of radiation, selectively expands antigen‑specific T cells and induces complete regression, mimicking the effect of high‑dose radiotherapy. Radiation increases intratumoral IFN‑β, activates hematopoietic cells and dendritic‑cell cross‑priming via autocrine IFN signaling, and the antitumor effect is lost in type I IFN‑nonresponsive hosts, demonstrating that type I IFN initiates a cascading innate and adaptive immune attack. Published in Cancer Research 71(7):2488–96, ©2011 AACR.

Abstract

Abstract The most widely held explanation for the efficacy of local radiotherapy (RT) is based on direct cytotoxicity to cancer cells through the induction of lethal DNA damage. Recent studies have shown that local ablative radiation of established tumors can lead to increased T-cell priming and T-cell–dependent tumor regression, but the underlying mechanism remains unclear. Here, we describe an essential role for type I IFN in local RT-mediated tumor control. We show that ablative RT increases intratumoral production of IFN-β and, more surprisingly, the antitumor effect of RT is abolished in type I IFN nonresponsive hosts. Furthermore, the major target of RT-induced type I IFN is the hematopoietic compartment. RT drastically enhances the cross-priming capacity of tumor-infiltrating dendritic cells (TIDC) from wild-type mice but not type I IFN receptor–deficient mice. The enhanced cross-priming ability of TIDCs after RT was dependent on autocrine production of type I IFNs. By using adenoviral-mediated expression of IFN-β, we show that delivery of exogenous IFN-β into the tumor tissue in the absence of RT is also sufficient to selectively expand antigen-specific T cells leading to complete tumor regression. Our study reveals that local high-dose RT can trigger production of type I IFN that initiates a cascading innate and adaptive immune attack on the tumor. Cancer Res; 71(7); 2488–96. ©2011 AACR.