Surgical Inflammation Alters Immune Response to Intraoperative Photodynamic Therapy
Richard W Davis1, Astero Klampatsa2, Gwendolyn M Cramer1
1Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Abstract:
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.
Significance:
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.
Insights
Combining surgery with photodynamic therapy (PDT) improves malignant pleural mesothelioma (MPM) outcomes. However, surgically induced inflammation may limit PDT
Area of Science:
- Oncology
- Immunology
- Surgical Oncology
Background:
- Malignant pleural mesothelioma (MPM) is challenging to treat, often requiring multi-modality approaches.
- Photodynamic therapy (PDT) is an intraoperative option for MPM, but its interaction with surgical effects is unclear.
- Surgical cytoreduction is crucial for MPM but may influence residual disease response.
Purpose of the Study:
- To investigate the impact of surgical-induced inflammation on the efficacy of photodynamic therapy (PDT) in malignant pleural mesothelioma (MPM).
- To determine if combining surgical cytoreduction with PDT offers curative potential in preclinical models.
- To explore the immunological consequences of combining surgery and PDT for MPM.
Main Methods:
- Utilized a murine model of MPM with surgical debulking (60-90% tumor removal).
- Administered Photofrin-based photodynamic therapy (PDT) post-surgery.
- Employed a tumor incision (TI) model to assess the effect of surgical inflammation on PDT efficacy.
- Evaluated antitumor immunity transfer via splenocytes and CD8+ T cells.
Main Results:
- PDT combined with surgical debulking demonstrated long-term response and curative potential in MPM murine models.
- Surgical incisions alone did not affect acute PDT cytotoxicity.
- Surgically induced inflammation significantly limited the generation of antitumor immunity by PDT.
- Immune cells from mice treated with TI followed by PDT transferred less antitumor immunity compared to PDT alone.
Conclusions:
- Combining PDT with surgical cytoreduction enhances long-term outcomes for MPM compared to surgery alone.
- Surgically induced inflammation can impede the development of antitumor immunity stimulated by PDT.
- Strategies to mitigate surgical immunosuppression may improve outcomes for intraoperative combined modality treatments in MPM.
