A Century of Radiation Therapy and Adaptive Immunity

Abstract

The coming of age for immunotherapy (IT) as a genuine treatment option for cancer patients through the development of new and effective agents, in particular immune checkpoint inhibitors, has led to a huge renaissance of an old idea, namely to harness the power of the immune system to that of radiation therapy (RT). It is not an overstatement to say that the combination of RT with IT has provided a new conceptual platform that has re-energized the field of radiation oncology as a whole. One only has to look at the immense rise in sessions at professional conferences and in grant applications dealing with this topic to see its emergence as a force, while the number of published reviews on the topic is staggering. At the time of writing, over 97 clinical trials have been registered using checkpoint inhibitors with RT to treat almost 7,000 patients, driven in part by strong competition between pharmaceutical products eager to find their market niche. Yet, for the most part, this enthusiasm is based on relatively limited recent data, and on the clinical success of immune checkpoint inhibitors as single agents. A few preclinical studies on RT–IT combinations have added real value to our understanding of these complex interactions, but many assumptions remain. It seems therefore appropriate to go back in time and pull together what actually has been a long history of investigations into radiation and the immune system (Figure 1) in an effort to provide context for this interesting combination of cancer therapies.

Tumor Size Matters—Understanding Concomitant Tumor Immunity in the Context of Hypofractionated Radiotherapy with Immunotherapy

“…This includes tumor neoantigen release [21], tumor adjuvant release (DAMPS) [22] and enhanced type I IFN signaling [23] leading to activation of dendritic cells and the antigen processing machinery, activation and clonal expansion of effector T cells at the tumor site (TILs) and elsewhere [24,25], and tumor death receptor upregulation [26]. There is a growing body of evidence that ICIs can enhance many of these RT-induced effects, with preclinical and occasional clinical reports of abscopal responses [3,27]. The ideal radiation dose and fractionation regimen for stimulating a systemic anti-tumor immune response remains controversial.…”

“…This also means that generating de novo tumor immunity is of paramount importance if the scope of successful IT is to be broadened. The possibility of integrating ICIs within radiation therapy (RT) of solid cancers is being intensely investigated in what can only be described an unprecedented number of clinical trials [3], but the efficacy of this combined approach is still uncertain. Furthermore, there are many features of the interaction of RT with the immune system in cancer therapy that need further elucidation.…”

Targeted and Off-Target (Bystander and Abscopal) Effects of Radiation Therapy: Redox Mechanisms and Risk/Benefit Analysis

“…, propensity to undergo apoptosis) of the various immune cell subsets, depending on the lineage, maturity, and activation status. B cells and naive T helper (Th) cells are radiation sensitive, whereas T memory cells, natural killer T cells, and regulatory T cells (Tregs) are more resistant ( 267 ). As presented in Figure 15 , the final balance between controlled immune response and excessive, pathologically chronic immunogenic response is not easily understood.…”

Modeling DNA damage-induced pneumopathy in mice: insight from danger signaling cascades

“…The high radiosensitivity of the normal lung tissue and its low repair capacity still remain major obstacles to successful RT or combined radiochemotherapy (RCT) of thorax-associated neoplasms. Furthermore, the interest in combining RT or RCT with immunotherapy may result in new and more severe complications [ 1 ].…”

“…renal ischemia/reperfusion injury [ 121 ], allograft reperfusion injury after transplantation [ 122 ] trauma [ 123 , 124 ], gout [ 125 ] and silica/asbestos induced injury [ 126 ] and these acute inflammatory pathways are also important to the development of organ fibrosis [ 103 , 119 ]. Importantly, danger signals from irradiated tissues can also activate downstream immune effector pathways to support cancer cure, or modulate acute and late adverse radiation effects (for a detailed review see [ 1 , 127 ]). Although several studies investigated the roles of additional PRR in BLM-induced fibrosis, e.g.…”