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Photodynamic therapy and anti-tumour immunity

Key Points

  • Photodynamic therapy (PDT) uses non-toxic dyes and harmless visible light in combination with oxygen to produce highly reactive oxygen species that kill cells.

  • In addition to destroying tumour tissue by a process that can produce cellular necrosis and the expression of stress proteins, PDT produces an acute inflammation, and attracts leukocytes to treated tumours.

  • PDT might increase the immunogenicity of dead tumour cells by exposing or creating new antigens, and by inducing heat-shock proteins that increase the efficiency of antigen cross-presentation to form more effective tumour-specific cytotoxic T cells.

  • The pro-inflammatory effects of PDT might increase dendritic-cell migration, antigen uptake and maturation.

  • PDT can produce tumour cures and long-lasting tumour-specific immunity (memory), as has been shown by the rejection of tumours on rechallenge in certain mouse and rat models.

  • PDT has been combined with a range of immunostimulatory therapies, including microbial adjuvants, to increase the anti-tumour immunity produced by PDT alone.

  • There are only a few reports of the immunostimulatory effects of PDT in humans, but increasing recognition of the effect should lead to further work and possibly to improved patient outcome.

Abstract

Photodynamic therapy (PDT) uses non-toxic photosensitizers and harmless visible light in combination with oxygen to produce cytotoxic reactive oxygen species that kill malignant cells by apoptosis and/or necrosis, shut down the tumour microvasculature and stimulate the host immune system. In contrast to surgery, radiotherapy and chemotherapy that are mostly immunosuppressive, PDT causes acute inflammation, expression of heat-shock proteins, invasion and infiltration of the tumour by leukocytes, and might increase the presentation of tumour-derived antigens to T cells.

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Figure 1: The mechanism of action on tumours in photodynamic therapy.
Figure 2: Photodynamic therapy induces activation of antigen-specific T cells.
Figure 3: Consequences of photodynamic therapy-induced inflammation.
Figure 4: Combination of photodynamic therapy with immunostimulants.
Figure 5: Mechanism of photodynamic therapy-induced immune suppression.

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Acknowledgements

A.P.C. was supported by a US Department of Defense CDMRP Breast Cancer Research Grant. M.R.H. was supported by the US National Institutes of Health. We thank T. N. Demidova for help and advice.

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Glossary

Neutropaenia

A reduction in numbers of circulating neutrophils that predisposes to infection.

Erysipelas

A skin disease caused by Streptococcus pyogenes.

Antigen

A macromolecule (usually a protein or polysaccharide) that is perceived as foreign and stimulates an immune response.

Major histocompatibility complex

Cell membrane proteins that bind short peptides and are recognized by T-cell receptors.

Innate immune response

The immediately available nonspecific defence against invading pathogens, which consists of cellular (neutrophils, macrophages and natural killer cells) and non-cellular (complement and antibacterial peptides) arms.

Adaptive immune response

An antigen-specific defence that develops with time, which consists of cellular (cytotoxic and helper T-lymphocytes) and humoral (B-lymphocytes and antibody) arms.

Fluence

The light energy delivered per unit area (J cm−2).

Fluence rate

The rate at which light energy is delivered per unit area (W cm−2).

Antigen-presenting cells

Phagocytic cells such as dendritic cells, macrophages and B cells, which take up foreign antigens, and present then through major histocompatibility complex class II and express co-stimulatory molecules to ensure an effective T-cell response.

Cross-presentation

The process by which exogenous antigens that would normally be presented by dendritic cells in the context of major histocompatibility complex (MHC) class II to CD4+ T cells are also presented in the context of MHC class I to CD8+ T cells.

Complement

A group of proteins in serum that function with antibodies (classical pathway) or in response to microbial stimuli (alternative pathway) to achieve the destruction of foreign blood cells or bacteria.

Toll-like receptors

First discovered in Drosophila, these represent a conserved set of pattern-recognition molecules that are triggered by motifs present on bacteria, viruses and fungi to initiate signalling which attracts and activates immune cells.

Hapten

A small reactive molecule that can bind to host proteins and stimulate an immune response.

Delayed type hypersensitivity

A delayed-onset, cytokine-induced localized inflammatory reaction characterized by a large influx of macrophages.

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Castano, A., Mroz, P. & Hamblin, M. Photodynamic therapy and anti-tumour immunity. Nat Rev Cancer 6, 535–545 (2006). https://doi.org/10.1038/nrc1894

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