Targeting immunogenic cancer cell death by photodynamic therapy: past, present and future

Abstract

The past decade has witnessed major breakthroughs in cancer immunotherapy. This development has been largely motivated by cancer cell evasion of immunological control and consequent tumor resistance to conventional therapies. Immunogenic cell death (ICD) is considered one of the most promising ways to achieve total tumor cell elimination. It activates the T-cell adaptive immune response and results in the formation of long-term immunological memory. ICD can be triggered by many anticancer treatment modalities, including photodynamic therapy (PDT). In this review, we first discuss the role of PDT based on several classes of photosensitizers, including porphyrins and non-porphyrins, and critically evaluate their potential role in ICD induction. We emphasize the emerging trend of ICD induction by PDT in combination with nanotechnology, which represents third-generation photosensitizers and involves targeted induction of ICD by PDT. However, PDT also has some limitations, including the reduced efficiency of ICD induction in the hypoxic tumor microenvironment. Therefore, we critically evaluate strategies for overcoming this limitation, which is essential for increasing PDT efficiency. In the final part, we suggest several areas for future research for personalized cancer immunotherapy, including strategies based on oxygen-boosted PDT and nanoparticles. In conclusion, the insights from the last several years increasingly support the idea that PDT is a powerful strategy for inducing ICD in experimental cancer therapy. However, most studies have focused on mouse models, but it is necessary to validate this strategy in clinical settings, which will be a challenging research area in the future.

Current Prospects for Treatment of Solid Tumors via Photodynamic, Photothermal, or Ionizing Radiation Therapies Combined with Immune Checkpoint Inhibition (A Review)

“…This third event, the triggering of inflammation and activation of the immune system, can last from days to weeks and can eventually exert a systemic (abscopal) effect; the latter constitutes the physiological basis for the concept of PDT-generated vaccines for cancer therapy [12,[43][44][45][46][47] Over the past decade, it has been realized that certain chemotherapeutic drugs and cancer therapies, such as PDT, PTT, and RT, induce a form of cell death which triggers an immune response, which is hence referred to as immunogenic cell death (ICD) [36,[47][48][49][50]. ICD activates innate and adaptive arms of the immune system, resulting in efficient elimination of tumors by generating long-term immunological memory [51,52]. The immune response generated by ICD is determined by the antigenicity and adjuvanticity of target cancer cells.…”

“…Over the past decade, it has been realized that certain chemotherapeutic drugs and cancer therapies, such as PDT, PTT, and RT, induce a form of cell death which triggers an immune response, which is hence referred to as immunogenic cell death (ICD) [ 36 , 47 , 48 , 49 , 50 ]. ICD activates innate and adaptive arms of the immune system, resulting in efficient elimination of tumors by generating long-term immunological memory [ 51 , 52 ]. The immune response generated by ICD is determined by the antigenicity and adjuvanticity of target cancer cells.…”

“…The ICD is usually accompanied by the release of adjuvant-like DAMPs which reside in the cells as a part of their normal functions, but once released, act as danger signals [ 53 , 54 ]. DAMPs, either secreted or exposed extracellularly on the surface of dying cells, are recognized by innate pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) expressed on immune cells, thereby promoting the recruitment of antigen-presenting cells (APCs) [ 50 , 52 ]. Dendritic cells (DCs), being the predominant APCs in most scenarios, take up and process the TSAs and present them to naïve T cells, thereby activating long-term adaptive immunity [ 36 ].…”

“…The anti-tumor effects of ICD are determined by the antigenicity and adjuvanticity of target cancer cells. While the antigenicity of tumor cells is determined by TSAs and tumor neoantigens (TNA), the adjuvant-like effects of ICD are mediated by the release of DAMPs [ 52 , 170 , 171 ]. A recent report by Lhuillier et al, using a 4T1 triple-negative murine breast tumor model, demonstrated radiotherapy-induced upregulation of the expression of genes containing immunogenic mutations in a poorly immunogenic model.…”

Intracellular Responses Triggered by Cold Atmospheric Plasma and Plasma-Activated Media in Cancer Cells

“…These molecules are normally retained within cells and integrated into their normal functioning, but once released outside the cells, they act as danger signals. The list of DAMPs includes calreticulin, heat shock proteins (HSPs) 70 and 90, high-mobility group box 1 (HMGB1), ATP, annexin A1, type I interferons (IFNs), mitochondrial DNA, and many other [116]. In this way, PAM rich in H 2 O 2 was shown to increase calreticulin exposure and ATP release in tumour cells [117].…”