Doix Bastien, Trempolec Natalia, Riant Olivier, Feron Olivier
Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Brussels, Belgium.
Institute of Condensed Matter and Nanosciences, Molecular Chemistry, Materials and Catalysis (IMCN/MOST), UCLouvain, Louvain-la-Neuve, Belgium.
Front Oncol. 2019 Aug 27;9:811. doi: 10.3389/fonc.2019.00811. eCollection 2019.
Recent studies have highlighted the potential of photodynamic therapy (PDT) to induce immunogenic cell death (ICD). The clinical use of photosensitizers (PS) to stimulate an anticancer immune response, and not to sterilize tumor cells, may however require some optimizations. Here, we examined how the dose of PS and the scheduling of PDT influence the generation of danger-associated molecular patterns proteins (DAMPs) and favor T cell antitumor activity. We found that upon photoactivation, a low dose of the non-porphyrinic PS OR141 was more prone than higher doses to induce DAMPs and to inhibit squamous cell carcinoma growth in mice. We further used PDT-killed cancer cells to prime dendritic cells (DC) and stimulate their maturation to evaluate whether the timing of their injection could influence the antitumor effects of radiotherapy. While PDT-based DC vaccination administered before radiotherapy failed to increase tumor growth inhibition, DC injection in the peri-radiotherapy period led to significant tumor growth delay, emphasizing the importance of the coincidence of T cell activation and alterations of the tumor bed. In conclusion, the use of OR141 as a bona fide ICD inducer led us to unravel both the non-linear relationship between PS concentration and PDT-induced antitumor immune response, and the value of an optimal timing of PDT when co-administered with conventional anticancer therapies. This study therefore stresses the necessity of adapting the clinical use of PDT when the goal is to promote an immune response and identifies PDT-based DC vaccination as a suitable modality to reach such objective.
近期研究突显了光动力疗法（PDT）诱导免疫原性细胞死亡（ICD）的潜力。然而，使用光敏剂（PS）来刺激抗癌免疫反应而非杀灭肿瘤细胞的临床应用可能需要一些优化。在此，我们研究了PS剂量和PDT方案如何影响危险相关分子模式蛋白（DAMP）的产生以及促进T细胞抗肿瘤活性。我们发现，光激活后，低剂量的非卟啉类PS OR141比高剂量更易于诱导DAMP并抑制小鼠鳞状细胞癌的生长。我们进一步使用经PDT处理杀死的癌细胞致敏树突状细胞（DC）并刺激其成熟，以评估注射时间是否会影响放射治疗的抗肿瘤效果。虽然放疗前进行基于PDT的DC疫苗接种未能增强肿瘤生长抑制作用，但在放疗期间注射DC导致肿瘤生长显著延迟，这强调了T细胞激活与肿瘤床改变同时发生的重要性。总之，将OR141用作真正的ICD诱导剂使我们揭示了PS浓度与PDT诱导的抗肿瘤免疫反应之间的非线性关系，以及与传统抗癌疗法联合使用时PDT最佳时间的价值。因此，本研究强调了在旨在促进免疫反应时调整PDT临床应用的必要性，并确定基于PDT的DC疫苗接种是实现这一目标的合适方式。
