Enhance the Immune Checkpoint Inhibitors Efficacy with Radiotherapy Induced Immunogenic Cell Death: A Comprehensive Review and Latest Developments

Simple Summary Efficient antitumoral immune response is conditioned by a regulated cell death called immunogenic cell death. Many immunologic cell death inducers are currently used in cancer treatment. Among them, radiation therapy is an adaptable, well tolerated and widely used modality of treatment in modern oncology. Moreover, there is growing evidence for synergistic mechanisms between radiotherapy and immune checkpoint inhibitors. Although pre-clinical concepts are numerous, robust clinical evidence is scarce. Radioimmunology is a rapidly evolving discipline with several ongoing clinical trials. In this review, we (i) explain the rationale behind radiotherapy and immune checkpoint-inhibitor association in the light of the most recent knowledge, (ii) provide the results of the latest clinical trials evaluating radiation therapy and immune checkpoint association and (iii) explore the future directions of radioimmunology research. The immunogenic cell death (ICD) is defined as a regulated cell death able to induce an adaptive immunity. It depends on different parameters including sufficient antigenicity, adjuvanticity and favorable microenvironment conditions. Radiation therapy (RT), a pillar of modern cancer treatment, is being used in many tumor types in curative, (neo) adjuvant, as well as metastatic settings. The anti-tumor effects of RT have been traditionally attributed to the mitotic cell death resulting from the DNA damages triggered by the release of reactive oxygen species. Recent evidence suggests that RT may also exert its anti-tumor effect by recruiting tumor-specific immunity. RT is able to induce the release of tumor antigens, to act as an immune adjuvant and thus to synergize with the anti-tumor immunity. The advent of new efficient immunotherapeutic agents, such as immune checkpoint inhibitors (ICI), in multiple tumor types sheds new light on the opportunity of combining RT and ICI. Here, we will describe the biological and radiobiological rationale of the RT-induced ICD. We will then focus on the interest to combine RT and ICI, from bench to bedside, and summarize the clinical data existing with this combination. Finally, RT technical adaptations to optimize the ICD induction will be discussed.

Automated summary

Efficient antitumoral immune response relies on immunogenic cell death, which can be induced by various factors including radiation therapy. The synergistic mechanisms between radiation therapy and immune checkpoint inhibitors are promising, but robust clinical evidence is still limited. Radioimmunology is a rapidly evolving field with numerous ongoing clinical trials.