The molecular basis of immuno-radiotherapy

Abstract

Purpose

Radiotherapy (RT) and immunotherapy are powerful anti-tumor treatment modalities. Experimental research has demonstrated an important interplay between the cytotoxic effects of RT and the immune system. This systematic review provides an overview of the basics of anti-tumor immunity and focuses on the mechanisms underlying the interplay between RT and immune anti-tumor response that set the molecular basis of immuno-RT.

Conclusions

An ‘immunity acquired equilibrium’ mimicking tumor dormancy can be achieved post-irradiation treatment, with the balance shifted toward tumor eradication or regrowth when immune cells’ cytotoxic effects or cancer proliferation rate prevail, respectively. RT has both immunosuppressive and immune-enhancing properties. The latter effect is also known as radio-vaccination. Its mechanisms involve up- or down-regulation of membrane molecules, such as PD-L1, HLA-class-I, CD80/86, CD47, and Fas/CD95, that play a vital role in immune checkpoint pathways and increased cytokine expression (e.g. INFα,β,γ, IL1,2, and TNFα) by cancer or immune cells. Moreover, the interactions of radiation with the tumor microenvironment (fibroblasts, tumor-infiltrating lymphocytes, monocytes, and dendritic cells are also an important component of radio-vaccination. Thus, RT may have anti-tumor vaccine properties, whose sequels can be exploited by immunotherapy agents to treat different cancer subtypes effectively.

Graphical Abstract

Keywords:

• Radiotherapy
• immunotherapy
• immune checkpoint molecules
• radio-vaccination
• anti-tumor immunity

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Notes on contributors

Ioannis M. Koukourakis

Ioannis M. Koukourakis, MD is a Radiation Oncology resident at Aretaieion University Hopsital and a PhD candidate at the National and Kapodistrian University of Athens. His research interests focus on the interactions between radiotherapy and the immune system.

Dina Tiniakos

Dina Tiniakos, MD PhD FRCPath is a Professor of Pathology & Director, Dept of Pathology, Aretaieion Hospital, Medical School, National & Kapodistrian University of Athens, Greece and academic pathologist at the Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, UK. She is past president of the European Society of Pathology and member, Scientific Advisory Board, Sharing Progress in Cancer Care.

Vassilis Kouloulias

Vassilis Kouloulias, MSc, MD, PhD, PhD, post-DOC is a Professor of Radiation Oncology & Scientific Director, Unit of Radiation Oncology, 2nd Dept of Radiology, ATTIKON University Hospital, Medical School, National & Kapodistrian University of Athens, Greece. Currently, Dr. Kouloulias is the President of the Greek Society of Radiation Oncologists, President of the Greek Society of Hyperthermic Oncology, member of the Scientific Advisory Group of ESTRO, member of experts’ board of the ASSISI European breast cancer think tank and member of the ESTRO-ESMO board for the implementation of clinical guidelines for radiotherapy in elderly patients with head and neck cancer.

Anna Zygogianni

Anna Zygogianni, MD, PhD is an Associate Professor of Radiation Oncology and Scientific Director of Radiotherapy Unit, Aretaieion University Hospital, Medical School, National & Kapodistrian University of Athens, Greece, Head of Cyberknife Unit, Secretary of the Greek society of Hyperthermic Oncology and from 2016 until now in charge of educational program for pre graduate study of Radiation Oncology Lectures of Medical School of Athens.