Surgical Inflammation Alters Immune Response to Intraoperative Photodynamic Therapy

Our plain-English summary of Surgical Inflammation Alters Immune Response to Intraoperative Photodynamic Therapy, by R.W. Davis, A. Klampatsa, G.M. Cramer, et al (Cancer Research Communications, 2023).

The study

• Authors: R.W. Davis, A. Klampatsa, G.M. Cramer, M.M. Kim, J.M. Miller, M. Yuan, C. Houser, E. Snyder, M. Putt, S.A. Vinogradov, S.M. Albelda, K.A. Cengel, T.M. Busch
• Journal: Cancer Research Communications
• Published: 2023;3(9):1810-1822
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Unlabelled: 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.

© 2023 The Authors; Published by the American Association for Cancer Research.

In plain English

This was a laboratory study in mice; it did not study asbestos. The authors grew two mouse mesothelioma cell lines (AB12 and AE17o) as tumors in the flank and combined surgery with photodynamic therapy (PDT), in which the drug Photofrin is activated by laser light. In female mice, PDT after 90% surgical removal of the tumor led to complete responses (no regrowth at 90 days) in 4 of 8 mice. To mimic surgical injury without removing tumor, the authors cut into tumors 4 hours before PDT. With PDT alone, 7 of 20 mice had complete responses. When the tumor was cut first, none of 8 mice did (P = 0.022). The incision did not change how well PDT killed tumor cells in the short term. Spleen cells from mice given incision then PDT slowed tumor growth in recipient mice less than spleen cells from mice given PDT alone. The authors concluded that PDT improves response to surgery, but that surgical injury has an immunosuppressive effect that blunts the antitumor effects of PDT. They noted that tumor incision does not exactly mimic chest surgery.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment: laboratory studies in two mouse models of mesothelioma, combining partial surgical removal or a tumor incision model with photodynamic therapy
• Who was studied: Mice with flank tumors grown from mouse mesothelioma cells. AB12 cells were grown in female 6–8-week-old BALB/c mice, and AE17o cells in C57BL/6 mice. Incision experiments were repeated in male BALB/c mice. Studies were approved at the University of Pennsylvania. Group sizes were mostly 5 to 20 mice.
• Exposure: No asbestos exposure was studied. Treatments were partial surgical removal of the tumor (30%, 60% or 90%) or a tumor incision without removal, made 4 hours before PDT. PDT used Photofrin 5 mg/kg followed 1 day later by 632 nm laser light at a total fluence of 135 J/cm2.
• Main results:
  • In female mice with AB12 tumors, PDT after 60% surgical debulking produced complete responses (no regrowth at 90 days) in 2 of 10 animals. PDT after 30% resection produced complete responses in 1 of 10.
  • In female mice with AB12 tumors, PDT after 90% resection produced complete responses in 4 of 8 mice.
  • In female mice with 80 mm3 AB12 tumors, PDT alone produced complete responses in 7 of 20 mice (35%). No complete responses occurred when the tumor was incised before PDT (P = 0.022).
  • The group given incision before PDT contained 8 mice, so none of 8 had a complete response, compared with 7 of 20 given PDT alone.
  • In male mice with AB12 tumors, complete responses occurred in 2 of 15 with PDT and 0 of 15 with incision then PDT (P = 0.040 for tumor regrowth rates).
  • When the incision was made immediately after PDT instead of before, the response did not differ from PDT alone: 6 of 23 complete responses versus 7 of 20.
  • The incision did not change tumor light properties, Photofrin levels or oxygenation at the time of PDT, and did not change the short-term killing of tumor cells by PDT.
  • In the AB12 model, spleen cells from mice given incision then PDT produced significantly smaller tumor growth delays in recipient mice than spleen cells from PDT-treated mice (P less than 0.001).
  • In the AE17o model in C57BL/6 mice, incision before PDT reduced the antitumor immunity of transferred CD8+ T cells (P = 0.0364) and of whole spleen cells (P = 0.0017), compared with PDT alone.
  • In the spleens of AB12 mice, CD11b+ Ly6G+ cells made up 3.79% of live cells after PDT, 5.74% after incision then PDT, and 2.46% with untreated tumors. The increase was significant for incision then PDT versus untreated (P = 0.019) but not for incision then PDT versus PDT. Regulatory T cells did not change.
• The authors' conclusion: The authors concluded that PDT significantly improves long-term response to surgical cytoreduction, but competes with an immunosuppressive effect of surgical injury that blunts the antitumor effects of PDT. They suggested that blocking IL6 or PGE2 around the time of surgery could be explored.
• Limitations the authors state:
  • Only mesothelioma tumor models were studied.
  • Models with tumors growing inside the ribcage (orthotopic models) could not be used, because tumors had to be incised or debulked in survival surgeries.
  • Tumor incision does not exactly mimic chest (intrathoracic) cytoreduction surgery.
  • The study used spleen cells rather than cells from the tumor microenvironment.
  • The partial resection approach involved human error in reducing tumors to the same size.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Inflammation, Cytoreductive Surgery, Pleural Mesothelioma, Mesothelioma.

Related studies

• A preclinical model to investigate the role of surgically-induced inflammation in tumor responses to intraoperative photodynamic therapy — R.W. Davis, E. Papasavvas, et al. (2018)
• PD-1 Blockade Mitigates Surgery-Induced Immunosuppression and Increases the Efficacy of Photodynamic Therapy for Pleural Mesothelioma — G.M. Cramer, R.W. Davis, et al. (2025)
• Phase III randomized trial of surgery with or without intraoperative photodynamic therapy and postoperative immunochemotherapy for malignant pleural mesothelioma — H.I. Pass, B.K. Temeck, et al. (1997)
• Radical pleurectomy and intraoperative photodynamic therapy for malignant pleural mesothelioma — J.S. Friedberg, M.J. Culligan, et al. (2012)
• Low-dose photodynamic therapy promotes vascular E-selectin expression in chest malignancies, improving immune infiltration and tumor control — L.E. Chriqui, D.N. Marie, et al. (2025)
• Photodynamic therapy and the evolution of a lung-sparing surgical treatment for mesothelioma — J.S. Friedberg, R. Mick, et al. (2011)

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