PD-1 Blockade Mitigates Surgery-Induced Immunosuppression and Increases the Efficacy of Photodynamic Therapy for Pleural Mesothelioma

Our plain-English summary of PD-1 Blockade Mitigates Surgery-Induced Immunosuppression and Increases the Efficacy of Photodynamic Therapy for Pleural Mesothelioma, by G.M. Cramer, R.W. Davis, E. Papasavvas, et al (Cancer Research Communications, 2025).

The study

• Authors: G.M. Cramer, R.W. Davis, E. Papasavvas, A. Klampatsa, J.M. Miller, S. Carter, R. Ikpe, M. Yuan, S. Widura, R.S. Majumdar, S. McNulty, M. Putt, A.V. Kossenkov, L.J. Montaner, S. Singhal, E.K. Moon, S.M. Albelda, K.A. Cengel, T.M. Busch
• Journal: Cancer Research Communications
• Published: 2025;5(5):841-856
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Unlabelled: Lung-sparing radical pleurectomy with intraoperative photodynamic therapy (PDT) demonstrates remarkable survival for patients with pleural mesothelioma. Nevertheless, most patients treated with this multimodal approach will develop local tumor recurrence. An understanding of potential causes of treatment failure is central to developing mitigation strategies. Surgery importantly reduces disease burden but also produces tumor-promoting inflammation, as demonstrated through transcriptomic analysis of pleural mesothelioma specimens. Using preclinical models in the setting of combination therapy, we separated the benefit of surgical resection from its counterproductive effects on therapeutic outcome. Specifically, we evaluated mechanisms by which surgically induced inflammation can be therapy-limiting in a murine model of tumor incision (TI) introduced by a surgical cut across the tumor. In this TI model, we identified distinct TI-altered patterns in innate and adaptive inflammatory cells in murine mesothelioma tumors, and we studied changes in these patterns with the addition of PDT. TI introduction of an immunosuppressive environment is established via upregulation of PD-1/PD-L1 expression on tumor cells, T cells, and myeloid cells that is partially resolved by PDT. Immune dysfunction is further mitigated by the addition of PD-1 blockade, leading to curative potential in a process that requires Ly6G+ neutrophils and CD8+ T cells. Overall, these studies suggest that, without PDT, surgical modulation of immune cell trafficking and functionality leads to systemic immunosuppression. This immunosuppressive state potentially interferes with the generation of antitumor immunity by PDT. However, targeted inhibition of surgery-induced signaling in the PD-l/PD-L1 pathway counteracts surgery's immunosuppressive outcomes to enhance PDT efficacy in the intraoperative setting.

Significance: Surgery combined with PDT extends survival for patients with mesothelioma, but these patients are still at risk for tumor recurrence, in part due to the immunosuppressive effects of surgery. We find, in a mouse model, that combining surgery, PDT, and immune checkpoint blockade maximizes the efficacy of these therapies.

©2025 The Authors; Published by the American Association for Cancer Research.

In plain English

This study combined gene-expression analysis of human pleural mesothelioma (PM) tissue with mouse experiments. Tumour specimens taken at intervals during lung-sparing pleurectomy, in a randomized phase II trial of intraoperative photodynamic therapy (PDT), were sequenced. In them, 708 genes changed significantly with time during surgery (FDR less than 5%), and IL-6 and IL-1 signalling were predicted to be activated (Z-scores 3.9 and 2.5). In mice with AB12 mesothelioma flank tumours, a tumour incision (TI) modelling surgical inflammation raised intratumoral IL-1Ra at 4 hours (P = 0.001). It also raised PD-L1 on tumour and stromal cells measured together and on some myeloid cells, raised PD-1 on T cells, and shortened median time to 400 mm3 to 7 versus 9 days (P = 0.025). In AE17O tumours, the difference (13 versus 14 days) was not significant. In AB12, PDT after TI gave 24 days, and adding anti-PD-1 gave beyond 90 days (P = 0.005). In AE17O, adding anti-PD-1 gave 26 versus 20.5 days (P = 0.025). Anti-PD-1 added to PDT alone gave no statistically significant improvement. In AB12 mice given TI, PDT and anti-PD-1, depleting Ly6G+ cells drastically reduced efficacy. Depleting CD8+ T cells removed the benefit in both models.

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: Laboratory study combining RNA sequencing of human tumour specimens from an ongoing randomized phase II surgical trial with mouse tumour experiments (tumour incision model, photodynamic therapy, antibody blockade and depletion)
• Who was studied: Human part: 80 PM specimens from 33 patients with epithelioid PM enrolled on trial NCT02153229 (surgeries June 2014 to June 2021), with analysis based on 72 specimens from 31 patients (26 male, 5 female; 27 epithelioid, 4 biphasic final histology). Mouse part: BALB/c mice with AB12 tumours and C57BL/6 mice with AE17O tumours
• Exposure: Surgical inflammation (macroscopic complete resection in patients; tumour incision without tissue removal in mice), Photofrin photodynamic therapy (5 mg/kg, 632 nm, 135 J/cm2, given 4 hours after incision), and anti-PD-1 (2.5 mg/kg), with anti-Ly6G or anti-CD8 depletion
• Main results:
  • In the human tumour specimens, 708 genes changed significantly with the time of collection during surgery (FDR less than 5%)
  • Pathway analysis of the human specimens predicted activation of IL-6 signalling (Z-score 3.9) and IL-1 signalling (Z-score 2.5) over the course of surgery
  • In AB12 mouse tumours, intratumoral IL-1Ra protein was higher 4 hours after tumour incision than in untreated tumour controls (P = 0.001)
  • In AB12 tumours, PD-L1 expression rose 24 hours after tumour incision in the CD45-negative population, which the authors describe as a combination of tumour and stromal cells measured together (P = 0.014)
  • In AB12 tumours, tumour incision increased PD-L1 on Ly6G-negative myeloid cells (macrophages/M-MDSCs) at 24 hours (P = 0.021)
  • In AB12 tumours, tumour incision increased PD-1 on all CD3+ cells at 2 days (P = 0.009), mainly on CD8+ T cells (P = 0.001) and NKT cells (P = 0.006)
  • Tumour incision alone shortened median AB12 tumour growth time to 400 mm3 to 7 days versus 9 days in untreated controls (P = 0.025); in AE17O the difference was not significant (13 vs 14 days, P = 0.057)
  • Anti-PD-1 after tumour incision alone gave a small increase in median time to 400 mm3 (7 to 11 days in AB12, P = 0.028; 13 to 17 days in AE17O, P less than 0.001)
  • PDT after tumour incision lengthened median tumour growth time: AB12 7 days (TI) versus 24 days (TI/PDT), AE17O 13 versus 20.5 days, both P less than 0.001
  • Adding anti-PD-1 to TI/PDT slowed regrowth: AB12 median survival greater than 90 days versus 24 days for TI/PDT (P = 0.005); AE17O 26 days versus 20.5 days (P = 0.025)
  • Anti-PD-1 added to PDT alone (no incision) gave no statistically significant additional improvement in either model (P = 0.56 in AB12; P = 0.79 in AE17O, medians 33.5 days for PDT vs 40 days for PDT/anti-PD-1)
  • In AB12 mice given TI/PDT/anti-PD-1, depletion of Ly6G+ neutrophils drastically reduced treatment efficacy and raised PD-L1 on Ly6C+ cells (P = 0.014); Ly6G depletion did not significantly change response to PDT alone (P = 0.57) or to TI/PDT
  • Ly6G depletion combined with TI/PDT (without anti-PD-1) did not affect therapeutic efficacy
  • CD8+ T-cell depletion removed the benefit of TI/PDT/anti-PD-1 in both models (AB12 P less than 0.001; AE17O P = 0.032)
• The authors' conclusion: The authors concluded that surgically induced inflammation creates an immunosuppressive state with increased PD-1/PD-L1 activity that limits PDT's antitumour immune effect, and that PD-1 blockade can counteract this and enhance PDT efficacy in the intraoperative setting
• Limitations the authors state:
  • The authors state the tumour incision model is both a strength and a limitation, as it likely produces less inflammation than actual surgical excision of tissue
  • Orthotopic mesothelioma models could not be used because tumours had to be incised during survival surgery
  • No fluctuations in IL-1alpha/IL-1beta transcription were seen at the time points studied, which the authors note may have peaked earlier

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Inflammation, Surgical Resection, Mesothelioma, PD-1/PD-L1, PD-L1.

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)
• Surgical Inflammation Alters Immune Response to Intraoperative Photodynamic Therapy — R.W. Davis, A. Klampatsa, et al. (2023)
• Modeling Epidermal Growth Factor Inhibitor-mediated Enhancement of Photodynamic Therapy Efficacy Using 3D Mesothelioma Cell Culture — G. Cramer, M. Shin, et al. (2019)
• A Novel Prospective Study Assessing the Combination of Photodynamic Therapy and Proton Radiation Therapy: Safety and Outcomes When Treating Malignant Pleural Mesothelioma — S.R. Rice, Y.R. Li, et al. (2019)
• 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)
• Safety and efficacy of PD-1/PD-L1 immune checkpoint inhibitors in patients with pre-treated advanced stage malignant mesothelioma: a systematic review and meta-analysis — A. Zafar, A.A. Rashid, et al. (2024)

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