Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Dermatology and Plastic Surgery Institute, Cleveland Clinic, Cleveland, OH, USA.
Photochem Photobiol. 2023 Mar;99(2):437-447. doi: 10.1111/php.13706. Epub 2022 Sep 20.
We previously showed that a combination of differentiation-inducing agents (5-fluorouracil [5FU], vitamin D3 or methotrexate) and aminolevulinate-based photodynamic therapy (PDT) improves clinical responses by enhancing protoporphyrin IX (PpIX) photosensitizer levels and cell death. Here, we show that in addition to its previously known effects, 5FU enhances PDT-induced tumor-regressing immunity. Murine actinic keratoses were treated with topical 5FU or vehicle for 3 days prior to aminolevulinic acid application, followed by blue light illumination (~417 nm). Lesions were harvested for time-course analyses of innate immune cell recruitment into lesions, i.e. neutrophils (Ly6G+) and macrophages (F4/80+), which peaked at 72 h and 1 week post-PDT, respectively, and were greater in 5FU-treated lesions. Enhanced infiltration of activated T cells (CD3+) throughout the time course, and of cytotoxic T cells (CD8+) at 1-2 weeks post-PDT, also occurred in 5FU-treated lesions. 5FU pretreatment reduced the presence of cells expressing the immune checkpoint marker PD-1 at ~72 h post-PDT, favoring cytotoxic T cell activity. A combination of 5FU and PDT, each individually known to induce long-term tumor-targeting immune responses in addition to their more immediate effects on cancer cells, may synergize to provide better management of squamous precancers.
我们之前曾表明，诱导分化剂（5-氟尿嘧啶[5FU]、维生素 D3 或甲氨蝶呤）和氨基酮戊酸基光动力疗法（PDT）的联合应用可通过提高原卟啉 IX（PpIX）光敏剂水平和细胞死亡来改善临床反应。在这里，我们表明，除了先前已知的作用外，5FU 还可增强 PDT 诱导的肿瘤消退免疫。在用氨基酮戊酸处理之前，用局部 5FU 或载体处理鼠光化性角化病 3 天，然后用蓝光照射（~417nm）。采集病变进行先天免疫细胞向病变内募集的时间过程分析，即中性粒细胞（Ly6G+）和巨噬细胞（F4/80+），分别在 PDT 后 72 小时和 1 周达到高峰，并且在 5FU 处理的病变中更大。在整个时间过程中，活化的 T 细胞（CD3+）和细胞毒性 T 细胞（CD8+）的浸润增强，在 PDT 后 1-2 周出现。5FU 预处理可减少在 PDT 后约 72 小时表达免疫检查点标志物 PD-1 的细胞的存在，有利于细胞毒性 T 细胞的活性。5FU 和 PDT 的联合应用，各自在除了对癌细胞的更直接影响之外，还能诱导长期的肿瘤靶向免疫反应，可能会协同作用，为鳞状前病变提供更好的治疗。
