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Review
. 2019 Jun 20;11(6):860.
doi: 10.3390/cancers11060860.

The 6th R of Radiobiology: Reactivation of Anti-Tumor Immune Response

Jihane Boustani  1 , Mathieu Grapin  2 , Pierre-Antoine Laurent  3 , Lionel Apetoh  4 , Céline Mirjolet  5   6
Affiliations
Review

The 6th R of Radiobiology: Reactivation of Anti-Tumor Immune Response

Jihane Boustani et al. Cancers (Basel). .

Abstract

Historically, the 4Rs and then the 5Rs of radiobiology explained the effect of radiation therapy (RT) fractionation on the treatment efficacy. These 5Rs are: Repair, Redistribution, Reoxygenation, Repopulation and, more recently, intrinsic Radiosensitivity. Advances in radiobiology have demonstrated that RT is able to modify the tumor micro environment (TME) and to induce a local and systemic (abscopal effect) immune response. Conversely, RT is able to increase some immunosuppressive barriers, which can lead to tumor radioresistance. Fractionation and dose can affect the immunomodulatory properties of RT. Here, we review how fractionation, dose and timing shape the RT-induced anti-tumor immune response and the therapeutic effect of RT. We discuss how immunomodulators targeting immune checkpoint inhibitors and the cGAS/STING (cyclic GMP-AMP Synthase/Stimulator of Interferon Genes) pathway can be successfully combined with RT. We then review current trials evaluating the RT/Immunotherapy combination efficacy and suggest new innovative associations of RT with immunotherapies currently used in clinic or in development with strategic schedule administration (fractionation, dose, and timing) to reverse immune-related radioresistance. Overall, our work will present the existing evidence supporting the claim that the reactivation of the anti-tumor immune response can be regarded as the 6th R of Radiobiology.

Keywords: immune response; radiotherapy fractionation; radiotherapy-immunotherapy association.

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Conflict of interest statement

Lionel Apetoh has performed consulting work for Roche, Bristol-Myers Squibb and Merck and receives a research grant from Sanofi. The other authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The reactivation of the immune response: the new R of radiobiology.
Figure 2
Figure 2
Radiotherapy in dependence of the fractionation schedule recruits different type of immune cells and can modulate the immunotherapy target expression. (Treg: regulatory T Cell; MDSC: Myeloid-derived suppressor cells; PD-L1: Programmed-Death Ligand 1; TIGIT: T-Cell immunoreceptor with Ig and ITIM domain; DNA: Desoxyribonucleic Acid; RT: Radiotherapy; T-REX: Three-Prime Repair Exonuclease). These results spring from Vanpouille-Box et al., Nature Com, 2017 and Grapin et al., JITC, in press.
Figure 3
Figure 3
According to the immune response induced by three types of fractionation schedules, we suggest optimized radio-chemo-immunotherapy protocols.
See this image and copyright information in PMC

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