Modulating Both Tumor Cell Death and Innate Immunity Is Essential for Improving Radiation Therapy Effectiveness

Abstract

Radiation therapy is one of the cornerstones of cancer treatment. In tumor cells, exposure to ionizing radiation (IR) provokes DNA damages that trigger various forms of cell death such as apoptosis, necrosis, autophagic cell death, and mitotic catastrophe. IR can also induce cellular senescence that could serve as an additional antitumor barrier in a context-dependent manner. Moreover, accumulating evidence has demonstrated that IR interacts profoundly with tumor-infiltrating immune cells, which cooperatively drive treatment outcomes. Recent preclinical and clinical successes due to the combination of radiation therapy and immune checkpoint blockade have underscored the need for a better understanding of the interplay between radiation therapy and the immune system. In this review, we will present an overview of cell death modalities induced by IR, summarize the immunogenic properties of irradiated cancer cells, and discuss the biological consequences of IR on innate immune cell functions, with a particular attention on dendritic cells, macrophages, and NK cells. Finally, we will discuss their potential applications in cancer treatment.

Reprogramming of Tumor-Associated Macrophages with Anticancer Therapies: Radiotherapy versus Chemo- and Immunotherapies

“…This was evidenced by increased mRNA levels for TNFα, IFNγ, IL-6, and IL-23 and higher protein levels for IL-1β and IL-8. While most of the previous studies showed the activation of NFκB p65 for macrophage reprogramming, this last study revealed that IR-induced M1-like phenotype was promoted by the transcriptional expression of IRF5 and was ataxia telangiectasia mutated (ATM)-dependent (107). Altogether, the results from in vitro experiment showed that unpolarized macrophages tend to acquire a M1 phenotype after MDI.…”

“…Moreover, modulators of DNA repair, such as Olaparib (PARP inhibitor), increased ATM activation and upregulated IRF5 transcription, resulting in macrophage activation toward a pro-inflammatory phenotype (107). In conclusion, IR is able to induce DNA damage by direct or ROS-dependent interactions with DNA.…”

“…This NOX2-dependent ATM activation controlled the polarization of Raw 264.7, THP-1 and hMDM in M1-like macrophages, through the regulation of IRF5 transcription. Moreover, in patients, the perturbation of ATM-dependent NOX2 signaling pathway was associated with a decreased iNOS macrophage number and poor tumor responses to radiotherapy (107). …”

“…In this study, the authors showed that macrophages acquired a M1-like phenotype after exposition to γ-irradiation (2 Gy). This polarization is made feasible by the activation of NOX2 and ATM, hence driving the transcription of IRF5 (107). While these results are very interesting, the contribution of IRF/STAT pathway to macrophage polarization mediated by irradiation needs to be further investigated in vivo and in patients.…”

Cancer Immunotherapy Getting Brainy: Visualizing the Distinctive CNS Metastatic Niche to Illuminate Therapeutic Resistance

“…Immune checkpoint blockers such as CTLA-4 and PD-1/PD-L1 enhance the antitumor response induced by radiation therapy (71,74,158–163); thus, the interplay between the biological effects of radiation therapy and the immune system may be a critical mechanism for inhibiting tumor growth and extending overall survival in brain metastasis patients. However, the ability to successfully design combination therapeutic strategies is limited due to a lack of understanding of the molecular and cellular mechanisms in radio-oncoimmunology (164). IVM’s spatiotemporal resolution overcomes limitations that constrain other techniques, enabling understanding of immune milieu changes following local or systemic treatment.…”