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Inflammatory microenvironment remodelling by tumour cells after radiotherapy

Nature Reviews Cancer volume 20, pages 203–217 (2020)Cite this article

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Abstract

The development of immune checkpoint inhibitors (ICIs) is revolutionizing the way we think about cancer treatment. Even so, for most types of cancer, only a minority of patients currently benefit from ICI therapies. Intrinsic and acquired resistance to ICIs has focused research towards new combination therapy approaches that seek to increase response rates, the depth of remission and the durability of benefit. In this Review, we describe how radiotherapy, through its immunomodulating effects, represents a promising combination partner with ICIs. We describe how recent research on DNA damage response (DDR) inhibitors in combination with radiotherapy may be used to augment this approach. Radiotherapy can kill cancer cells while simultaneously triggering the release of pro-inflammatory mediators and increasing tumour-infiltrating immune cells – phenomena often described colloquially as turning immunologically ‘cold’ tumours ‘hot’. Here, we focus on new developments illustrating the key role of tumour cell-autonomous signalling after radiotherapy. Radiotherapy-induced tumour cell micronuclei activate cytosolic nucleic acid sensor pathways, such as cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING), and propagation of the resulting inflammatory signals remodels the immune contexture of the tumour microenvironment. In parallel, radiation can impact immunosurveillance by modulating neoantigen expression. Finally, we highlight how tumour cell-autonomous mechanisms might be exploited by combining DDR inhibitors, ICIs and radiotherapy.

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Fig. 1: Crosstalk between cGAS–STING, inflammasome and ribonucleic acid sensing pathways.
Fig. 2: Radiation-induced micronucleus formation and the role of the DNA damage response.
Fig. 3: Tumour cell-centric immune signalling in the tumour microenvironment post radiotherapy.

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Acknowledgements

The authors acknowledge support from the Rosetrees Trust, the Oracle Cancer Trust, the Anthony Long Charitable Trust, the Wellcome Trust, the Stoneygate Trust and the Royal Marsden/Institute of Cancer Research NIHR Biomedical Research Centre.

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Authors and Affiliations

  1. Targeted Therapy Team, The Institute of Cancer Research, London, UK

    Martin McLaughlin, Emmanuel C. Patin, Magnus T. Dillon & Kevin J. Harrington

  2. Translational Immunotherapy Team, The Institute of Cancer Research, London, UK

    Malin Pedersen & Alan A. Melcher

  3. The Royal Marsden Hospital, London, UK

    Anna Wilkins, Magnus T. Dillon, Alan A. Melcher & Kevin J. Harrington

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  1. Martin McLaughlin
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  4. Anna Wilkins
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The authors contributed equally to all aspects of the article.

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Correspondence to Martin McLaughlin.

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Competing interests

A.A.M. reports research grant funding from AstraZeneca/Medimmune, Bristol Myers Squibb and Oncolytics Biotech; and advisory board membership, honoraria and/or speakers’ bureaus from Amgen, AstraZeneca, Bristol-Myers-Squibb, Merck-Serono and Turnstone Biologics. K.J.H. reports research grant funding from AstraZeneca/Medimmune, Boehringer-Ingelheim, Merck Sharp Dohme and Replimune; and advisory board membership, honoraria and/or speakers’ bureaus from Amgen, AstraZeneca, Bristol-Myers-Squibb, Boehringer-Ingelheim, Merck-Serono, Merck Sharp Dohme, Oncolys, Pfizer and Replimune. The other authors declare no competing interests.

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Nature Reviews Cancer thanks S. Demaria, R. Greenberg and R. Weichselbaum for their contribution to the peer review of this work.

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Supplementary information

Glossary

Immune checkpoint inhibitors

(ICIs). Therapeutic blockade of negative immune checkpoint signalling. Most notable of these are the clinically approved agents targeting cytotoxic T lymphocyte-associated protein 4 (CTLA4) and programmed cell death protein 1 ligand 1 (PD-L1)–programmed cell death protein 1 (PD-1).

Tumour neoantigens

Neoantigens can arise when mutations in tumour cells alter peptide fragments presented to the immune system. The immune system can recognize these as foreign versus the non-mutated self-sequence.

Subclonal neoantigens

Subclonal neoantigens are only present in a subset of tumour cells.

Cyclic GMP–AMP

(cGAMP). Mammalian 2′,3′-cyclic guanosine monophosphate–adenosine monophosphate, shortened to cGAMP, is a second messenger produced by cyclic GMP–AMP synthase (cGAS) binding to cytosolic DNA. It is frequently called an immunotransmitter owing to extensive indirect signalling.

Pattern recognition receptors

Innate immune receptors that recognize viral or microbial molecules (pathogen-associated molecular patterns (PAMPs)) or host cell molecules released during damage (damage-associated molecular patterns (DAMPs)) activating host immune signalling.

Type I interferon

(IFN). This class of interferons includes IFNα isoforms and IFNβ. IFNα/β receptor 1 (IFNAR1) and IFNAR2 form the type I IFN receptor.

Exosomes

Extracellular vesicles released from cells and shown to contain proteins, lipids, RNA and/or DNA. They are thought to act as a means of intercellular communication through transmission of bioactive macromolecules.

Gap junctions

Intercellular channels composed of connexin transmembrane proteins. They permit direct cell–cell transfer of ions and small molecules.

Ectoenzyme

An enzyme that is found on the cell surface or that is secreted and functions outside a cell.

HIN domains

DNA binding domains present on interferon (IFN)γ-inducible protein 16 (IFI16) and absent in melanoma 2 (AIM2) that facilitate recognition of cytosolic double-stranded DNA. HIN is an acronym for haematopoietic expression, interferon-inducible nature and nuclear localization.

Inflammasome

A multiprotein intracellular complex that activates the pro-inflammatory cytokines interleukin 1β (IL-1β) and IL-18. This can be due to pathogens or sterile stimuli leading to activation of caspase 1.

Pyroptosis

A highly inflammatory form of cell death resulting from inflammasome activation of caspase 1.

Micronuclei

Small nuclear structures formed by mitotic errors or chromosome breakage. They form within a nuclear envelope isolated from the primary nucleus.

Chromothripsis

Clustered chromosomal rearrangements in one or a few chromosomes, which are thought to occur through a one-step catastrophic genomic event.

STING-associated vasculopathy with onset in infancy

(SAVI). An autoinflammatory disorder driven by activating mutations in stimulator of interferon genes (STING).

Aicardi-Goutières syndrome

(AGS). An inflammatory disorder driven by numerous mutations (TREX1, SAMHD1, RNASEH2A–C, ADAR1 and IFIH1) that lead to increased activation of cytoplasmic nucleic acid sensors and type I interferon production.

Fanconi anaemia

A rare genetic disorder that results in aplastic anaemia, leukaemia and cancer susceptibility, and hypersensitivity to DNA cross-linking agents. The pathway is responsible for the repair of DNA interstrand cross-links and overlaps somewhat with homologous recombination repair.

Homologous recombination repair

(HRR). An identical or nearly identical DNA sequence from a homologous chromosome is used as a template for the repair of a DNA break.

Antigen

In this context, a major histocompatibility complex I (MHC-I)-presented peptide capable of stimulating an immune response.

Major histocompatibility complex I

(MHC-I). A complex composed of an α and β chain expressed on all nucleated cells. MHC-I presents peptide fragments of intracellular proteins to the immune system.

Radiation-upregulated neoantigens

Radiation can increase existing tumour neoantigens through either radiation-induced transcription or increased antigen presentation. It is also possible for radiotherapy to create neoantigens owing to DNA damage-induced mutations.

SIINFEKL

A peptide sequence from chicken ovalbumin presented by major histocompatibility complex I (MHC-I) and used as a model peptide to study antigen presentation.

Clonal neoantigen

A clonal neoantigen is a tumour antigen present in all tumour cells, as opposed to a subclonal neoantigen present in only a subset of tumor cells.

Damage-associated molecular patterns

(DAMPs). Stimuli released by stressed, dying or injured cells that may trigger an inflammatory response by the activation of numerous pattern recognition receptors.

Hypofractionated radiotherapy

Radiation treatment where the total dose of radiation is divided into larger doses and given over a smaller number of fractions than standard radiation therapy.

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McLaughlin, M., Patin, E.C., Pedersen, M. et al. Inflammatory microenvironment remodelling by tumour cells after radiotherapy. Nat Rev Cancer 20, 203–217 (2020). https://doi.org/10.1038/s41568-020-0246-1

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