Targeting Innate Immunity to Enhance the Efficacy of Radiation Therapy

Abstract

Radiation continues to play a major role in the treatment of almost every cancer type. Traditional radiation studies focused on its ability to damage DNA, but recent evidence has demonstrated that a key mechanism driving the efficacy of radiation in vivo is the immune response triggered in irradiated tissue. Innate immune cells including macrophages, dendritic cells, and natural killer cells are key mediators of the radiation-induced immune response. They regulate the sensing of radiation-mediated damage and subsequent radiation-induced inflammation. Given the importance of innate immune cells as determinants of the post-radiation anti-tumor immune response, much research has been devoted to identify ways to both enhance the innate immune response and prevent their ability to suppress ongoing immune responses. In this review, we will discuss how the innate immune system shapes anti-tumor immunity following radiation and highlight key strategies directed at the innate immune response to enhance the efficacy of radiation.

Keywords: NK cells; dendritic cells; immunotherapy; innate and adaptive immune response; macrophages; radiation therapy.

Figure 1

Model of immune activation following RT. RT induces direct tumor cell death which leads to release of various immunological mediators in the form of ATP, HMGB1, calreticulin, and complement (A). This leads to innate immune cell priming, where innate immune cells, such as dendritic cells and macrophages, recognize these mediators through various receptors, migrate to the tumor (B) and induce the production of inflammatory molecules such as TNF-α, IL-1β, and type I IFN (C). Innate cells then migrate to the lymphoid tissue (D) carrying antigens acquired from the tumor cell for presentation (E) resulting in activation of the adaptive immune response and elimination of tumors. Once tumors are eradicated, the RT-induced inflammation is suppressed (F), and tissue damage associated with tumors and the immune response is repaired (G).

Figure 2

Innate immune signals (“danger signals”) triggered by RT. RT induces the release and activation of multiple different inflammatory mediators from injured cells including complement, heat shock protein 70 (hsp70), high-mobility group box protein 1 (HMGB1), cytosolic DNA, calreticulin, and adenosine triphosphate (ATP). These molecules are sensed by innate immune cells such as macrophages or dendritic cells via toll-like receptor 4 (TLR-4), cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING), CD47 and NLR family pyrin domain containing protein 3 (NLRP3). Once sensed these receptors send signals via nuclear factor kappa B (NF-κB) and interferon regulatory factor 3 (IRF3) leading to downstream cytokine production and subsequent inflammation.