Painless Photodynamic Therapy Triggers Innate and Adaptive Immune Responses in a Murine Model of UV‐induced Squamous Skin Pre‐cancer

Abstract

Painless photodynamic therapy (p-PDT), which involves application of photosensitizer and immediate exposure to light to treat actinic keratosis (AK) in patients, causes negligible pain on the day of treatment but leads to delayed inflammation and effective lesion clearance (Kaw et al., J Am Acad Dermatol 2020). To better understand how p-PDT works, hairless mice with UV-induced AK were treated with p-PDT and monitored for 2 weeks. Lesion clearance after p-PDT was similar to clearance after conventional PDT (c-PDT). However, lesion biopsies showed minimal cell death and less production of reactive oxygen species (ROS) in p-PDT treated than in c-PDT-treated lesions. Interestingly, p-PDT triggered vigorous recruitment of immune cells associated with innate immunity. Neutrophils (Ly6G+) and macrophages (F4/ 80+) appeared at 4 h and peaked at 24 h after p-PDT. Damage-associated molecular patterns (DAMPs), including calreticulin, HMGB1, and HSP70, were expressed at maximum levels around 24 h post-p-PDT. Total T cells (CD3+) were increased at 24 h, whereas large increases in cytotoxic (CD8+) and regulatory (Foxp3+) T cells were observed at 1 and 2 weeks post-p-PDT. In summary, the ability of p-PDT to eliminate AK lesions, despite very little overt cellular damage, appears to involve stimulation of a local immune response.

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

“…However, there could be great value in considering these modalities side by side, i.e., comparing the ability of each treatment to stimulate anti-tumor immunity, and asking whether those changes are leveraged by ICI administered at the appropriate time, resulting in improved therapeutic outcomes. A recent study by our group, in addition to a few studies by others, demonstrated that anti-tumor immunity generated by PDT may play a relatively larger role in the therapeutic outcomes, as compared to direct PDT-induced cell death within the primary tumor, than was previously thought [ 17 , 18 , 19 , 20 , 21 ]. This has major implications because the development of long-term anti-tumor immunity is the desired outcome and ultimate goal for generating durable cancer cures.…”

“…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 list of DAMPs is continuously growing and includes calreticulin (CRT), high-mobility group box 1 (HMGB1), heat shock proteins (HSPs) 70 and 90, and ATP as some of the common members activated following PDT [ 21 , 53 , 54 ].…”

“…Neutrophils, being the most predominant leukocytes early on, have been reported to accumulate in high numbers within less than 5 min following PDT, and remain present at the site until 24 h post-PDT [ 21 , 57 ]. In addition to infiltrating treated tumors, neutrophils have also been reported to accumulate in tumor-draining lymph nodes (DLN).…”

“…Another class of immune cell in the TME is macrophages, also referred to as tumor-associated macrophages (TAMs), which differentiate from monocytes and acquire an ability to activate immune effector functions following PDT [ 21 , 66 , 67 , 68 ]. In an unperturbed tumor microenvironment, the majority of macrophages belong to an anti-inflammatory M2 phenotype that promotes immunosuppression, growth, angiogenesis and metastasis.…”

“…Similarly, the adoptive transfer of CD8+ T cells from PDT-cured animals protected naïve recipients from cancer cells of the same origin [ 82 ]. PDT-induced elevations in the number of CD8+ T cells and increases in their antigen-specific cytotoxic activities have been reported in several preclinical studies; for example, Abdel-Hady et al reported a direct correlation between treatment response and increased levels of CD8+ cells in lesions following PDT [ 19 , 21 , 60 , 83 , 84 ].…”