Harnessing the Immunological Effects of Radiation to Improve Immunotherapies in Cancer

Abstract

Ionizing radiation (IR) is used to treat 50% of cancers. While the cytotoxic effects related to DNA damage with IR have been known since the early 20th century, the role of the immune system in the treatment response is still yet to be fully determined. IR can induce immunogenic cell death (ICD), which activates innate and adaptive immunity against the cancer. It has also been widely reported that an intact immune system is essential to IR efficacy. However, this response is typically transient, and wound healing processes also become upregulated, dampening early immunological efforts to overcome the disease. This immune suppression involves many complex cellular and molecular mechanisms that ultimately result in the generation of radioresistance in many cases. Understanding the mechanisms behind these responses is challenging as the effects are extensive and often occur simultaneously within the tumor. Here, we describe the effects of IR on the immune landscape of tumors. ICD, along with myeloid and lymphoid responses to IR, are discussed, with the hope of shedding light on the complex immune stimulatory and immunosuppressive responses involved with this cornerstone cancer treatment. Leveraging these immunological effects can provide a platform for improving immunotherapy efficacy in the future.

Keywords: cancer; immunity; immunogenic cell death; immunotherapies; radiation.

Figure 1

Immunogenic cell death elicited by IR. ICD induced by IR is marked by the release of DAMPs (HMGB1, double-stranded DNA and RNA, HSP70, ATP and calreticulin (CRT)), Type I IFN (IFN-α and IFN-β) through cGAS-STING signaling and other cytokines (TNF-α, IL-1ß and IL-6) and chemokines (CCL2 and CCL5) through STING-induced NF-κB activation. Broken lines indicate movement and continuous lines represent the production of the given target.

Figure 2

Key immune stimulatory and immunosuppressive events associated with IR treatment in cancer. Following IR, ICD results in the release of DAMPs, cytokines, chemokines and tumor antigens which activate APCs and induce the mass infiltration of myeloid and lymphoid cells. Three key immunological events occur following ICD which dictate the treatment response: (1) APCs internalize, process and present tumor antigens released by damaged tumor cells and migrate to the tumor draining lymph node to present these antigens to CD4⁺ and CD8⁺ T cells. (2) CD8⁺ T cells with receptors specific to the tumor antigen localize to the tumor and kill cancers via the cytolytic enzymes perforin and granzyme B, along with the cytotoxic cytokines IFN-γ and TNF-α. (3) Immunosuppressive macrophages and MDSCs suppress APC function through a variety of means, including IL-10 expression, which depletes MHC II on their surface, TGF-β, which polarizes CD4+ T cells to Tregs, Arginase, which degrades L-argining, a valuable metabolite for T cell function, and ROS, which also impair T cell function. Neutrophils also utilize arginase and ROS to mitigate T cell function.