Surgical Inflammation Alters Immune Response to Intraoperative Photodynamic Therapy.
Surgical Inflammation Alters Immune Response to Intraoperative Photodynamic Therapy.
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DOI：
10.1158/2767-9764.crc-22-0494
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发表时间：
2023-09
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恶性胸膜间皮瘤(MPM)患者的外科细胞减少术是多种治疗策略的一部分。我们小组此前曾将光动力疗法(PDT)的临床应用描述为MPM的一种术中治疗选择。虽然手术对于去除大量疾病是必要的，但手术对残留的MPM负担的影响尚不清楚。在这项床边到工作台的研究中，基于Photofrin的PDT引入了在手术去除60%至90%的MPM肿瘤的小鼠模型中实现长期反应的可能性。因此，PDT的补充提供了不完全切除后的治疗潜力。尽管取得了这一成功，我们推测，手术诱导炎症可能会减轻残留病对进一步治疗的综合反应。利用先前证实的肿瘤切开(TI)模型，我们证明了手术切开的引入对光动力疗法的急性细胞毒性没有影响。然而，我们发现手术引起的炎症限制了PDT抗肿瘤免疫的产生。与单纯PDT相比，当TI先于小鼠肿瘤的PDT时，治疗小鼠的脾细胞和/或CD8+T细胞向受体动物传递的抗肿瘤免疫较少。这些结果表明，与单纯细胞减少相比，在手术中加入PDT可显著提高长期疗效，但同时，手术引起的炎症可能会限制PDT产生的抗肿瘤免疫。这些数据为未来旨在阻断手术诱导的免疫抑制的潜在方法提供了信息，这些方法可能会改善术中联合治疗的结果。虽然间皮瘤很难治疗，但我们已经证明，将手术与一种形式的放射、光动力疗法相结合，可能会帮助间皮瘤患者活得更长。在这项研究中，我们在小鼠身上证明了这种方案可以通过解决作为手术副产品而引起的炎症来进一步改进。
Surgical cytoreduction for patients with malignant pleural mesothelioma (MPM) is used for selected patients as a part of multi-modality management strategy. Our group has previously described the clinical use of photodynamic therapy (PDT), a form of non-ionizing radiation, as an intraoperative therapy option for MPM. Although necessary for the removal of bulk disease, the effects of surgery on residual MPM burden are not understood. In this bedside-to-bench study, Photofrin-based PDT introduced the possibility of achieving a long-term response in murine models of MPM tumors that were surgically debulked by 60% to 90%. Thus, the addition of PDT provided curative potential after an incomplete resection. Despite this success, we postulated that surgical induction of inflammation may mitigate the comprehensive response of residual disease to further therapy. Utilizing a previously validated tumor incision (TI) model, we demonstrated that the introduction of surgical incisions had no effect on acute cytotoxicity by PDT. However, we found that surgically induced inflammation limited the generation of antitumor immunity by PDT. Compared with PDT alone, when TI preceded PDT of mouse tumors, splenocytes and/or CD8+ T cells from the treated mice transferred less antitumor immunity to recipient animals. These results demonstrate that addition of PDT to surgical cytoreduction significantly improves long-term response compared with cytoreduction alone, but at the same time, the inflammation induced by surgery may limit the antitumor immunity generated by PDT. These data inform future potential approaches aimed at blocking surgically induced immunosuppression that might improve the outcomes of intraoperative combined modality treatment. Although mesothelioma is difficult to treat, we have shown that combining surgery with a form of radiation, photodynamic therapy, may help people with mesothelioma live longer. In this study, we demonstrate in mice that this regimen could be further improved by addressing the inflammation induced as a by-product of surgery.