Open access Review J Immunother Cancer: first published as 10.1136/jitc-2020-001926 on 11 January 2021. Downloaded from Targeting immunogenic cancer cell death by photodynamic therapy: past, present and future Razan Alzeibak,1 Tatiana A. Mishchenko,1 Natalia Y. Shilyagina,1 Irina V. Balalaeva,1 1 1,2,3 Maria V. Vedunova, Dmitri V. Krysko To cite: Alzeibak R, ABSTRACT James P. Allison and T. Honjo for revealing Mishchenko TA, Shilyagina NY, The past decade has witnessed major breakthroughs the specific molecular players in immune et al. Targeting immunogenic in cancer immunotherapy. This development has been surveillance and formulating a strategy for cancer cell death by largely motivated by cancer cell evasion of immunological photodynamic therapy: past, using checkpoint inhibitors as a potential control and consequent tumor resistance to conventional 1 2 present and future. Journal cancer therapy. for ImmunoTherapy of Cancer therapies. Immunogenic cell death (ICD) is considered one of the most promising ways to achieve total tumor Over the past decade emerged the concept 2021;9:e001926. doi:10.1136/ of immunogenic cell death (ICD), a cell jitc-2020-001926 cell elimination. It activates the T-cell adaptive immune response and results in the formation of long-term death modality that stimulates innate and adaptive immune responses resulting in ► Additional material is immunological memory. ICD can be triggered by many published online only. To view, anticancer treatment modalities, including photodynamic the generation of long-term immunological please visit the journal online therapy (PDT). In this review, we first discuss the role memory.3–5 The immunogenicity of cancer (http:// dx. doi. org/ 10. 1136/ jitc- of PDT based on several classes of photosensitizers, cell death is dictated by the antigenicity and 2020- 001926). including porphyrins and non-porphyrins, and critically adjuvanticity of dying cancer cells.3 6 The evaluate their potential role in ICD induction. We antigenicity of tumor cells is determined emphasize the emerging trend of ICD induction by PDT RA and TAM are joint first by the presence of tumor-associated anti- authors. in combination with nanotechnology, which represents third-genera tion photosensitizers and involves targeted gens (TAA) and tumor neoantigens (TNA). MVV and DVK are joint senior induction of ICD by PDT. However, PDT also has some However, they usually fail to drive efficient authors. limitations, including the reduced efficiency of ICD immunity in the absence of additional adju- Accepted 02 December 2020 induction in the hypoxic tumor microenvironment. vants required for the recruitment and acti- Therefore, we critically evaluate strategies for overcoming vation of antigen-presenting cells (APC). this limitation, which is essential for increasing PDT ICD has an adjuvant- like effect mediated http://jitc.bmj.com/ efficiency. In the final part, we suggest several areas for by the release of damage-associated molec- future research for personalized cancer immunotherapy, ular patterns (DAMPs). These molecules including strategies based on oxygen-boosted PDT and are normally retained within cells and inte- nanoparticles. In conclusion, the insights from the last several years increasingly support the idea that PDT is a grated in their normal functioning, but once powerful strategy for inducing ICD in experimental cancer released outside the cells, they act as danger 7 8 © Author(s) (or their therapy. However, most studies have focused on mouse signals. DAMPs can be actively secreted, on September 24, 2021 by guest. Protected copyright. employer(s)) 2021. Re- use models, but it is necessary to validate this strategy in permitted under CC BY- NC. No passively released extracellularly or exposed commercial re- use. See rights clinical settings, which will be a challenging research area on the dying cell surface. It is believed that and permissions. Published by in the future. emitted DAMPs promote the recruitment BMJ. and maturation of APCs (eg, dendritic cells) 1 Institute of Biology and INTRODUCTION and thereby mediate presentation of TAA Biomedicine, Lobachevsky State and TNA to effector CD8 T cells. The list University of Nizhny Novgorod, The proper functioning of the immune Nizhny Novgorod, Russian system has a pivotal role in prevention of of DAMPs is still expanding and includes Federation cancer initiation, progression and therapy. calreticulin (CRT), heat shock proteins 2 Cell Death Investigation and The role of the immune system in cancer (HSPs) 70 and 90, high- mobility group box Therapy Laboratory (CDIT), therapy has been widely studied, and the 1 (HMGB1), ATP, annexin A1, type I inter- Department of Human Structure 3 9 10 and Repair, Ghent University, modern paradigm of anticancer therapy ferons (IFNs) and mitochondrial DNA. Ghent, Belgium has accepted the notion that interaction of These molecules differ in origin, function, 3Cancer Research Institute dying/dead cancer cells with immune cells is cell localization, release mechanism and Ghent, Ghent, Belgium a crucial factor determining cancer treatment stage of death at which they are released.11–13 Correspondence to efficiency. The Nobel Prize in Physiology or The ability of cancer therapy to induce ICD Professor Dmitri V. Krysko; Medicine in 2018 reflects the significance of is clinically important because ICD stimu- dmitri. krysko@ ugent. be immunotherapy. The prize was awarded to lates anticancer immune responses that are Alzeibak R, et al. J Immunother Cancer 2021;9:e001926. doi:10.1136/jitc-2020-001926 1 Open access J Immunother Cancer: first published as 10.1136/jitc-2020-001926 on 11 January 2021. Downloaded from critical for the efficacy of the therapy and long- term anti- Box 1 Historical background of photodynamic therapy (PDT): cancer immunity.14–17 from fundamental studies to clinical practice Recently, much attention has been given to ICD, which can be induced by different stimuli and anti- Discovery and development of PDT cancer treatment modalities, including chemotherapy A mechanism discovered in 1900 in Munich, Germany by Oscar Raab, with anthracyclines and oxaliplatin, radiotherapy, UVC who worked under the supervision of Professor Herman von Tappeiner, irradiation, oncolytic viruses and photodynamic therapy laid the basis of PDT. Studies on the effect of different dyes on protozo- (PDT).4 10 15 18 19 The ICD induced by various stimuli can an viability helped him to notice that light irradiation of infusoria in the differ in the DAMPs’ profile and has also been linked to presence of acridine red dye leads to infusoria’s death. Interestingly, different cell death modalities such as apoptosis, necro- the observed effect was more pronounced in comparison with light ir- ptosis20–22 and ferroptosis.23 24 In this review, we first radiation alone and with the dye action in the dark. Oscar Raab and discuss the role of PDT in the induction of ICD and then Hermann von Tappeiner initially linked this phenomenon to light energy transfer to the dye, similar to photosynthesis.110 Dr H. Tappeiner pub- assess the advantages and disadvantages of PDT in the lished research,111 in which he first suggested the possibility of using induction of ICD. Finally, we discuss possible strategies the photodynamic effect for medical purposes (the historical name of for enhancing the ICD- inducing potential of PDT- based the mechanism is associated with light action on the dynamics—mo- anticancer therapies. bility—of cells; the term was introduced in 1907). In 1907, Dr Jodlbauer and Dr Tappeiner proved that the development of photodynamic reactions requires the presence of oxygen in their MAIN PRINCIPLES OF PDT environment.112 PDT of cancer involves the systemic, local or topical PDT in clinical practice administration of a non- toxic, light- sensitive dye known The use of the photodynamic effect in practice started only a few de- as a photosensitizer (PS). After the PS accumulates selec- cades later. In 1948, Figge summarized a series of studies showing that tively in the tumor, it is excited by illumination with visible exogenously injected porphyrins can selectively accumulate in murine light of appropriate wavelength. In the presence of molec- tumors.113 In these years, suggestions emerged for the possibility of ular oxygen in cells and tissues, this leads to the gener- using porphyrins to detect malignancies in the body. In 1955, Schwartz ation of cytotoxic species and stimulation of signaling obtained a purified mixture of hematoporphyrins known as hematopor- pathways, which consequently leads to cell death and phyrin derivative (HpD), the first generation of photosensitizers. In 1978, 25 Thomas Dougherty’s team (Roswell Park Cancer Institute, Buffalo, New tumor tissue destruction. PDT was first applied in the 114 clinic in 1903 (box 1) and then it became widely used York, USA) used HpD to treat tumors of various localizations. Later, in 1980, Dougherty synthesized from HpD the drug Photofrin, a mixture to treat several types of cancer.25–29 It is noteworthy that of hematoporphyrin oligomers connected to each other by ester and PDT is currently also used to treat some autoimmune30 31 32 complex ester linkages. At the same time, Photofrin analogs were ob- and infectious diseases. Very recently, cetuximab sara- tained in different countries, including Photosan (Germany), Photogem tolacan was approved by the Japanese government for the (Russia), Hiporfin and Deuteporfin.115–117 Since the 1980s, there has treatment of locally advanced or recurrent head and neck been a rapid development of PDT, including the development of new 33 http://jitc.bmj.com/ cancer. This is the first PS conjugated to an antibody; it drugs and capabilities for their application. Photosensitizers of different consists of the water-soluble silicon- phthalocyanine deriv- chemical nature are being developed,118 and areas of PDT application ative, IRDye700DX (IR700), conjugated to cetuximab. are expanding: anticancer therapy, acne,119 antimicrobial therapy,32 120 121 122 Cetuximab, which is approved by the FDA, targets the psoriasis, atherosclerosis, herpes and age-rela ted macular 123 epidermal growth factor receptor, which is overexpressed degeneration.