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The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence

An Erratum to this article was published on 24 July 2015

This article has been updated

Key Points

  • Radiotherapy is a common treatment option for cancer patients. However, many aspects of the tumour microenvironment (TME) can render a tumour resistant to radiotherapy de novo or can lead it to recur with a worse prognosis following therapy.

  • Normal tissue toxicity limits the dose of radiotherapy that can be safely delivered.

  • Combination strategies are required in order to achieve better tumour control.

  • Radiotherapy-mediated immunogenic cell death (ICD) can elicit an immune response, but antitumour immunity may be limited owing to the presence of radioresistant suppressor cell types in the TME. Combining radiotherapy and immunomodulatory treatments may overcome adaptive immune suppression and holds great promise both locally in the primary tumour and abscopally.

  • Hypoxia has a crucial role in radioresistance owing to reduced oxygen-mediated fixation of DNA damage and hypoxia induced factor 1α (HIF1α)-mediated cell survival. Attempts to increase oxygen delivery, normalize tumour vessels, inhibit HIF1α and prevent the recruitment of bone marrow-derived cells (BMDCs) required for vasculogenesis are all being tested to reduce tumour hypoxia, improve radiotherapy responses and prevent tumour recurrence after therapy.

  • Tumour irradiation induces a wound healing response that is characterized by inflammation, cancer-associated fibroblast (CAF) modulation and extracellular matrix (ECM) remodelling, which may facilitate tumour recurrence. Targeting the initial inflammatory response may counteract attempts to boost the immune-mediated antitumour response following radiotherapy. Therefore, reducing ECM remodelling by inhibiting growth factors, receptor kinases or matrix enzymes may be more effective in preventing the post-irradiation stiffening of the TME that could facilitate tumour spread.

  • Careful scheduling of tumour reoxygenation strategies with radiotherapy will be required to maximize tumour control. Subsequent inclusion of immunomodulatory and anti-fibrotic treatments should be considered to maximize therapeutic benefits and to prevent post-irradiation tumour recurrence and metastasis.

Abstract

Radiotherapy plays a central part in curing cancer. For decades, most research on improving treatment outcomes has focused on modulating radiation-induced biological effects on cancer cells. Recently, we have better understood that components within the tumour microenvironment have pivotal roles in determining treatment outcomes. In this Review, we describe vascular, stromal and immunological changes that are induced in the tumour microenvironment by irradiation and discuss how these changes may promote radioresistance and tumour recurrence. We also highlight how this knowledge is guiding the development of new treatment paradigms in which biologically targeted agents will be combined with radiotherapy.

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Figure 1: Radiation effects on the TME.
Figure 2: Biological effects and normal tissue toxicity after radiotherapy.
Figure 3: ICD of cancer cells and immune tolerization.
Figure 4: Targets for radiosensitization.
Figure 5: The interconnected radiotherapy-mediated changes in the TME.

Change history

  • 24 July 2015

    In the version of this article that was originally published, there was an error in Figure 1 on page 410 and in Figure 4 on page 417. In both figures, programmed cell death protein 1 (PD1) was shown to be expressed on the cancer cell and PD1 ligand 1 (PDL1) was shown to be expressed on T cells, whereas PD1 should be expressed on T cells and PDL1 on cancer cells. These errors have now been corrected in the online versions of the article.

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Acknowledgements

The authors acknowledge support from Cancer Research UK programme grants C46/A10588 and C7224/A13407, the Wellcome Trust, the NIHR Royal Marsden/Institute of Cancer Research Biomedical Research Centre, Oracle Cancer Trust, Rosetrees Trust and Anthony Long Trust.

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Glossary

COMMA-D cells

An epithelial cell line derived from the mammary tissue of a mid-pregnant BALB/c mouse, which exhibits many characteristics distinctive of normal mammary epithelial cells.

Atherosclerosis

Thickening of the artery wall as a result of white blood cell invasion and accumulation.

Medial necrosis

Necrosis of the middle portion of vessel walls (anatomically called the tunica media).

Vessel co-option

A mechanism by which tumours obtain a blood supply by hijacking the existing vasculature.

Microvascular injury

Injury to the fine network of blood vessels and capillaries that results in changed patterns of blood flow.

Desmoplastic reaction

A stromal reaction that can be induced by tissue injury, wound repair or cancer growth. Increased extracellular matrix and growth factor production and secretion result in the formation of scar-like fibrotic tissue.

Adaptive immunity

A carefully regulated, adaptable, specific immune response comprising humoral- and cell-mediated components. It is capable of both systemic actions and immunological memory to specific stimuli. It is triggered by known antigens or by appropriate antigen presentation from the innate immune system.

Tumour associated macrophages

(TAMs). Macrophages within the tumour microenvironment; they are generally immunosuppressive and resemble the alternatively activated M2 macrophage.

Regulatory T cells

(TReg cells). A T cell subset that exerts immunosuppressive and tolerizing effects. TReg cells have an important role in cancer immune editing, in the maintenance of a permissive cancer microenvironment and in preventing effective adaptive immune recognition of tumour cells.

Innate immune system

The initial immune response that occurs in a generic manner to inflammatory stimuli, comprising complement activation and immune cell recruitment and activation. It coordinates the activation of the adaptive immune system by antigen presentation.

Direct and indirect radiation effects

Radiation damage can be divided into direct effects, where the damage is a result of the ionizing radiation itself, and indirect effects, which refer to the resultant changes in cellular pathways as a result of radiation: for example, as a result of reactive oxygen species.

Damage-associated molecular patterns

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

Pathogen-associated molecular patterns

(PAMPs). Signalling from pathogens by particular stimuli that can be recognized by immune cells, leading to an inflammatory response.

Immunogenic cell death

Cell death that triggers an immune reaction by DAMP–PRR signalling. This may occur as a result of different types of tissue damage; for example, damage caused by radiotherapy or chemotherapy.

Immune tolerization

The recognition of 'self' and 'non-self' during antigen presentation is important and carefully regulated to prevent autoimmunity, it is the process of recognizing antigens as 'self'.

Abscopal effects

Irradiation of tumour cells or the adjacent extracellular matrix can induce biologically relevant changes in distant cells, which may or may not have been irradiated themselves. These are distinguished from bystander (which refers to changes affecting nearby unirradiated cells) and cohort effects (which refer to changes affecting off-target irradiated cells).

Eccrine

A type of tumour from secretory sweat glands.

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Barker, H., Paget, J., Khan, A. et al. The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat Rev Cancer 15, 409–425 (2015). https://doi.org/10.1038/nrc3958

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