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Immunomodulation by radiotherapy in tumour control and normal tissue toxicity

Nature Reviews Immunology volume 22, pages 124–138 (2022)Cite this article

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Abstract

Radiotherapy (RT) is a highly effective anticancer treatment that is delivered to more than half of all patients with cancer. In addition to the well-documented direct cytotoxic effects, RT can have immunomodulatory effects on the tumour and surrounding tissues. These effects are thought to underlie the so-called abscopal responses, whereby RT generates systemic antitumour immunity outside the irradiated tumour. The full scope of these immune changes remains unclear but is likely to involve multiple components, such as immune cells, the extracellular matrix, endothelial and epithelial cells and a myriad of chemokines and cytokines, including transforming growth factor-β (TGFβ). In normal tissues exposed to RT during cancer therapy, acute immune changes may ultimately lead to chronic inflammation and RT-induced toxicity and organ dysfunction, which limits the quality of life of survivors of cancer. Here we discuss the emerging understanding of RT-induced immune effects with particular focus on the lungs and gut and the potential immune crosstalk that occurs between these tissues.

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Fig. 1: Timeline of acute and chronic effects of radiotherapy on tissue components.
Fig. 2: Radiotherapy-induced chronic inflammation and fibrosis of the lungs.
Fig. 3: Immune aspects of radiotherapy-induced chronic inflammation and intestinal damage.
Fig. 4: Potential homing signals regulating immune crosstalk between the mucosal sites of the lungs and gut.

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Acknowledgements

U.M.C., K.J.W., T.M.I. and J.H. are supported by Cancer Research UK via RadNet Manchester (C19941/A28701). K.J.W. and T.M.I. are also supported by Cancer Research UK via the Cancer Research UK Manchester Centre (C147/A25254), and T.M.I. and J.H. are also supported by a Cancer Research UK Programme Grant (C431/A28280). T.M.I. is also supported by the NIHR Manchester Biomedical Research Centre (NIHR-BRC-1215-20007). M.A.T. is funded by the UK Biotechnology and Biological Sciences Research Council, the UK Medical Research Council, the Kenneth Rainin Foundation and the UK Defence Science and Technology Laboratory. D.P.D. is supported by the Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (218570/Z/19/Z). The Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, is supported by core funding from the Wellcome Trust (203128/Z/16/Z).

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Authors and Affiliations

  1. Lydia Becker Institute for Immunology and Inflammation, Wellcome Centre for Cell-Matrix Research, Manchester Collaborative Centre for Inflammation Research, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK

    Urszula M. Cytlak, Douglas P. Dyer & Mark A. Travis

  2. Targeted Therapy Group, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK

    Urszula M. Cytlak, Jamie Honeychurch & Timothy M. Illidge

  3. Division of Pharmacy and Optometry, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK

    Kaye J. Williams

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  1. Urszula M. Cytlak
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  2. Douglas P. Dyer
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  3. Jamie Honeychurch
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  4. Kaye J. Williams
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  5. Mark A. Travis
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All authors contributed substantially to the discussion of the content, the writing of the article and the review and/or editing of the manuscript.

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Correspondence to Urszula M. Cytlak, Mark A. Travis or Timothy M. Illidge.

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Glossary

Tumour microenvironment

(TME). A tumour-associated niche made up of a collection of stromal cells comprised of immune cells, endothelial cells and fibroblasts, structural components like extracellular matrix as well as signalling components including cytokines, chemokines and growth factors.

Abscopal responses

Systemic immune responses that are triggered following radiotherapy applied to a local tumour site. Such responses are believed to be propagated mainly by dendritic cell and CD8+ T cell responses, and lead to control of secondary tumour at distal tissue sites outside the initial radiotherapy area.

Immune checkpoint inhibitors

Clinically used monoclonal antibodies targeting specific regulatory immune cell receptors that are important for maintaining self-tolerance and limiting inflammatory responses. Certain cancer cells use these so-called checkpoint immune pathways to evade host immunity. The main immune checkpoint inhibitors used as anticancer immunotherapy target cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD1) or its ligand (PDL1).

Sterile inflammation

An inflammation induced in the absence of a pathogenic threat, instead being triggered by tissue damage and release of danger-associated molecular patterns (DAMPs). Release of DAMPs leads to recruitment of immune cells, which are required to clear damaged cells and initiate the tissue repair. Sometimes, sterile inflammation might become excessive and result in pathology, like in radiotherapy-induced damage and breakdown of mucosal barriers.

RT-induced cell death

Following exposure to ionizing radiation, cells can undergo cellular death primarily due to DNA damage. Different types of radiotherapy (RT)-induced cell death are described for different types of cells and cancers depending on their molecular profile. These include death by necrosis, apoptosis or autophagy. Importantly, each of these types of death has the ability to initiate a cascade of immune signalling following the release of damage-associated molecular patterns.

M1-like macrophage phenotype or an M2-like macrophage phenotype

‘M1’ and ‘M2’ are classifications historically used to define macrophages activated in vitro as pro-inflammatory (when ‘classically’ activated with interferon-γ (IFNγ) and lipopolysaccharide) or anti-inflammatory (when ‘alternatively’ activated with IL-4 or IL-10), respectively. However, macrophages in vivo are highly specialized and heterogeneous with regard to their phenotypes and functions, which are continuously shaped by their tissue microenvironment. Therefore, the M1–M2 classification is too simplistic to explain the true nature of macrophages in vivo, although these terms are still often used to indicate whether the macrophages in question are more pro-inflammatory or anti-inflammatory.

NLRP3 inflammasome

An important regulator of inflammatory responses that can be triggered by a wide range of danger and inflammatory stimuli. This intracellular multimolecular complex acts via the activation of caspases leading to secretion of the pro-inflammatory cytokines IL-1β and IL-18.

Cancer-associated fibroblasts

A heterogeneous group of mesenchymal cells found in the tumour microenvironment that have crucial roles in tumour initiation, progression and metastasis. They can inhibit antitumour immunity by expressing immune checkpoint molecules and by supporting regulatory T cell responses in tumours.

Myeloid-derived suppressor cells

A type of myeloid cells that can be attracted to the tumour microenvironment. These cells often have an immunosuppressive phenotype and provide the tumour with protection from host immunity by hindering antitumour effector T cell responses. The myeloid-derived suppressor cells can be of monocytic phenotype (CD11b+LY6C+GR1+ in mice and CD11b+CD14+CD15−HLA-DRlow in humans) or granulocytic/polymorphonuclear phenotype (CD11b+LY6G+GR1+ in mice and CD11b+CD14−CD15+ in humans).

Endothelial-to-mesenchymal transition

A process that together with epithelial-to-mesenchymal transition is the driver of endothelial and epithelial progenitor and mesenchymal stem cell differentiation into myofibroblasts in response to either endothelial or epithelial signals as part of normal wound healing of these two barrier sites. Both endothelial-to-mesenchymal transition and epithelial-to-mesenchymal transition can be accelerated by radiotherapy and transforming growth factor-β (TGFβ) and are implicated in the late normal tissue toxicity and fibrosis of irradiated organs.

Clinical target volume

A volume of a tissue or organ that contains the clinically visible area of the gross tumour volume or subclinical malignant growth with a small area of surrounding normal tissue. Radiotherapy is directed to the clinical target volume rather than just the gross tumour volume to ensure the best tumour control. In certain cases, such a clinical target volume will encompass the primary tumour and the local draining lymph nodes.

Mitotic catastrophe and delayed cell senescence

Mitotic catastrophe is a type of radiotherapy-induced cell death in which the cell prematurely enters mitosis or is trapped in a cell cycle arrest for a prolonged time. The resultant aberrant mitosis or ‘delayed senescence’ leads to cells that are still metabolically active but can acquire chromosomal aberrations or a pro-inflammatory phenotype (senescence-associated secretory phenotype) or even leads to the development of secondary cancerous sites, and thus contributes to long-term irradiation toxicity. Some cells trapped in these states will die over time via one of the cellular death pathways (necrosis, apoptosis or autophagy). The full mechanism and the extent of deleterious effects following these cellular arrests remain unknown.

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Cytlak, U.M., Dyer, D.P., Honeychurch, J. et al. Immunomodulation by radiotherapy in tumour control and normal tissue toxicity. Nat Rev Immunol 22, 124–138 (2022). https://doi.org/10.1038/s41577-021-00568-1

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