Photodynamic therapy and anti-tumour immunity

Abstract

The principle of photodynamic therapy (PDT) was first proposed over 100 years ago1. A recent review in Nature Reviews Cancer by Rakesh Jain and colleagues described some of the historical milestones in the development of PDT as a cancer treatment2. Many of the photosensitizers (PSs) that have been studied since PDT was first proposed are based on a porphyrin-like nucleus3. PSs function as catalysts when they absorb visible light and then convert molecular oxygen to a range of highly reactive oxygen species (ROS). The ROS that are produced during PDT have been shown to destroy tumours by multifactorial mechanisms4,5 (FIG. 1). PDT has a direct affect on cancer cells, producing cell death by necrosis and/or apoptosis6. PDT also has an affect on the tumour vasculature, whereby illumination and ROS production causes the shutdown of vessels and subsequently deprives the tumour of oxygen and nutrients7,8. Finally, PDT also has a significant effect on the immune system9–11, which can be either immunostimulatory or immunosuppressive.

Figure 1

The mechanism of action on tumours in photodynamic therapy

The photosensitizer (PS) absorbs light and an electron moves to the first short-lived excited singlet state. This is followed by intersystem crossing, in which the excited electron changes its spin and produces a longer-lived triplet state. The PS triplet transfers energy to ground-state triplet oxygen, which produces reactive singlet oxygen (1O2). 1O2 can directly kill tumour cells by the induction of necrosis and/or apoptosis, can cause destruction of tumour vasculature and produces an acute inflammatory response that attracts leukocytes such as dendritic cells and neutrophils.

Most of the commonly used cancer therapies are immunosuppressive. Chemotherapy and ionizing radiation delivered at doses sufficient to destroy tumours are known to be toxic to the bone marrow, which is the source of all cells of the immune system, and neutropaenia and other forms of myelosuppression are often the dose-limiting toxicity of these therapies. However, it should be noted that low doses of either ionizing radiation12,13 or chemotherapy14 can have immunostimulatory effects, including the induction of heat-shock proteins15. Less well known is the fact that major surgery can also have an immunosuppressive effect that leads to a significant diminution of lymphocyte and natural killer (NK) cell function16. The ideal cancer therapy would not only destroy the primary tumour, but at the same time trigger the immune system to recognize, track down and destroy any remaining tumour cells, be they at or near the site of the primary tumour or distant micrometastases. PDT, in common with some other local cancer therapies such as cryotherapy17 and hyperthermia18, might have these desirable properties.

The importance of the immune system in the host response against cancer has been studied for many years, but immunotherapy is only accepted as a treatment option in a few cases. More than 700 cases of spontaneous regression in advanced tumours in patients have been reported19, including malignant melanoma, hepatocellular carcinoma, lung metastases after destruction of the primary renal cell carcinoma and Hodgkin disease. Moreover, such spontaneous regressions normally occur following an infection.

Cancer immunotherapy (even if unrecognized as such) has a long history. The Egyptians noted that surgical opening of the tumour site could produce tumour regression, one would assume through the generation of infection and activation of the immune system20. Over 100 years ago a surgeon from New York, William Coley21, discovered that some infections could produce tumour regression, and he created a ‘vaccine’ based initially on erysipelas-causing bacteria22. The bacillus Calmette–Guerin (BCG) vaccine derived from Mycobacterium bovis has been used to prevent tuberculosis since 1921, and has been applied for immunostimulation in neoplasia since the 1960s. The most effective use of this treatment is for superficial bladder cancer23.

Since these early studies, groundbreaking discoveries in immunology have identified the roles of lymphocyte classes and subclasses24, dendritic cells and antigen presentation25, interleukins (IL) and other cytokines26, and tumour-associated antigens and major histocompatibility complex (MHC) molecules27 in mediating the anti-tumour immune response. However, most cancers avoid or escape immune control28,29, and death from metastatic cancer is still the most likely result. In this Review we discuss the effect of PDT on the anti-tumour immune response, and the role of PDT in stimulating and suppressing both the innate immune response and adaptive immune response. We also summarize the available data on combinations of PDT with other immunostimulatory therapies.