Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Cancer Res Commun. 2023 Sep 11;3(9):1810-1822. doi: 10.1158/2767-9764.CRC-22-0494. eCollection 2023 Sep.
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.
外科细胞减灭术用于恶性胸膜间皮瘤（MPM）患者，作为多模式管理策略的一部分，用于选定的患者。我们的小组之前曾描述过光动力疗法（PDT）的临床应用，这是一种非电离辐射形式，作为 MPM 的术中治疗选择。尽管手术对于去除大量疾病是必要的，但手术对残留 MPM 负担的影响尚不清楚。在这项从床边到临床的研究中，基于 Photofrin 的 PDT 为 MPM 肿瘤的小鼠模型提供了实现长期反应的可能性，这些肿瘤通过 60%至 90%的手术去块。因此，PDT 的添加提供了不完全切除后的治愈潜力。尽管取得了这一成功，我们还是假设手术引起的炎症可能会减轻对进一步治疗的残留疾病的全面反应。利用以前验证过的肿瘤切口（TI）模型，我们证明手术切口的引入对 PDT 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 产生的抗肿瘤免疫。与单独 PDT 相比，当 TI 先于 PDT 治疗小鼠肿瘤时，来自治疗小鼠的脾细胞和/或 CD8 T 细胞向受体动物转移的抗肿瘤免疫较少。这些结果表明，与单独细胞减灭术相比，将 PDT 加入外科细胞减灭术可显著改善长期反应，但与此同时，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引起的免疫抑制的潜在方法提供了信息，这可能会改善术中联合治疗的结果。
尽管间皮瘤难以治疗，但我们已经表明，将手术与光动力疗法等放射形式结合使用可能有助于间皮瘤患者活得更长。在这项研究中，我们在小鼠中证明，通过解决手术产生的炎症，可以进一步改善这种方案。
