Low-dose photodynamic therapy promotes vascular E-selectin expression in chest malignancies, improving immune infiltration and tumor control

Our plain-English summary of Low-dose photodynamic therapy promotes vascular E-selectin expression in chest malignancies, improving immune infiltration and tumor control, by L.E. Chriqui, D.N. Marie, A. Sifis, et al (Journal for Immunotherapy of Cancer, 2025).

The study

• Authors: L.E. Chriqui, D.N. Marie, A. Sifis, C. Gattlen, M. Ortolini, Y. Hao, O. De Souza Silva, E. Abdelnour-Berchtold, M. Gonzalez, T. Krueger, L. Liaudet, E. Meylan, S. Berezowska, M. Christodoulou, T. Losmanova, R.W. Peng, T.M. Marti, J. Joyce, S. Cavin, J.Y. Perentes
• Journal: Journal for Immunotherapy of Cancer
• Published: 2025;13(6)
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Chest malignancies such as non-small cell lung cancer (NSCLC) or pleural mesothelioma (PM) have an ominous prognosis. Photodynamic therapy (PDT) of NSCLC and PM improves patient survival, but the precise underlying mechanism remains unknown. Here, we hypothesized that low-dose PDT (L-PDT) alters the expression of tumor endothelial cell adhesion molecules favoring immune cell recruitment and tumor control. We explored this hypothesis in two mouse models of NSCLC and PM. We validated our findings in 82 PM patient samples.

Methods: We assessed, in C56BL/6 mice bearing 344SQ-NSCLC and in BALB/c mice bearing AB12-PM, how L-PDT (400 μg/kg Visudyne administered intravenously, irradiance: 50 mW/cm2, light dose: 10 J/cm2) affected tumor growth, modulated the tumor immune microenvironment and the expression of endothelial selectin cell adhesion molecule (E-selectin) using real-time multiphoton imaging, immunofluorescence staining and flow cytometry. We then blocked E-selectin, canonical nuclear factor kappa B (NF-κB) pathway or selectively depleted CD8+ lymphocytes with dedicated peptides/antibodies in mouse models to evaluate the effect of L-PDT on tumors. Finally, we assessed in 82 PM patient samples the correlation between vascular E-selectin and CD8+ lymphocyte content by immunofluorescence staining of tissue sections and their association with patient survival.

Results: L-PDT induced vascular E-selectin in both NSCLC and PM, which enhanced granzyme B+/CD3+/CD8+ lymphocyte infiltration and improved tumor control. Blockade of E-selectin or immunodepletion of CD8+ lymphocytes abrogated the L-PDT-mediated cancer regression. Moreover, canonical NF-κB pathway blockade impaired enhanced vascular E-selectin expression and CD8+ T cells infiltration in tumors following L-PDT. In human malignant pleural mesothelioma samples, we found a correlation between vascular E-selectin and CD8+ T cell infiltration, which was associated with improved patient outcome.

Conclusion: L-PDT remodels the vasculature of chest tumors and favors a cytotoxic immune microenvironment promoting tumor control. This approach could complement current immunotherapy approaches in these malignancies.

© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.

In plain English

This laboratory study used mice, human vessel-lining cells and 82 pleural mesothelioma patients' tumor samples. Asbestos was not studied, though AB12 mouse mesothelioma cells came from crocidolite asbestos-exposed mice. The authors tested low-dose photodynamic therapy (L-PDT), in which an injected drug is light-activated, in mice with pleural mesothelioma or non-small cell lung cancer. Tumor vessel E-selectin doubled in both models one day after treatment versus untreated tumors. Flow cytometry showed tumor CD8+ T cells (immune cells) rose significantly by day 5 in both models, but on day 1 only in mesothelioma mice. Median survival with L-PDT was 10 and 47 days, versus 6 and 34 without, in mesothelioma and lung cancer mice respectively. Blocking E-selectin stopped the immune-cell rise and tumor-control and survival gains in both models. Removing CD8+ cells cancelled these gains in mesothelioma mice. Among 21 patients given chemotherapy and surgery (not L-PDT), median survival was 24 months if vessel E-selectin rose between biopsy and surgery (n=13), versus 8 months if it fell or stayed stable (n=8). These are associations. The authors concluded this supports testing L-PDT in mesothelioma patients.

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 animal experiments in two mouse tumor models, cell-culture experiments on human endothelial cells, and analysis of tumor tissue samples from patients with pleural mesothelioma
• Who was studied: Mice with tumors grown in the chest: C57BL/6 mice with 344SQ non-small cell lung cancer, and BALB/c mice (including T-cell-deficient nude mice) with AB12 pleural mesothelioma. Also immortalized human vascular endothelial cells (EC-RF24). Tumor samples from 82 pleural mesothelioma patients (105 samples in total; 54 epithelioid, 21 biphasic, 7 sarcomatoid), from the University Hospital of Bern plus five from Lausanne University Hospital, Switzerland. 21 patients had surgery and similar chemotherapy, with matched pre-treatment biopsy and post-treatment surgical samples. Collection dates are not given.
• Exposure: The exposure studied in mice and cells was low-dose photodynamic therapy (L-PDT): Visudyne (benzoporphyrin derivative), a light-activated drug, at 400 µg/kg given intravenously, then light at 50 mW/cm2 to a dose of 10 J/cm2. Asbestos exposure was not studied; the AB12 mouse mesothelioma cell line was derived from crocidolite asbestos-exposed BALB/c mice. The patients did not receive L-PDT; their samples came from biopsy and from surgery after chemotherapy.
• Main results:
  • In both mouse models, L-PDT caused a significant twofold increase in tumor vessel E-selectin on day 1 compared with untreated controls, and the effect was maintained up to day 5.
  • On immunofluorescence, L-PDT significantly increased tumor CD8+ T cells, including granzyme B+ CD8+ T cells, in both mouse models.
  • On flow cytometry, tumor CD8+ T cell content was significantly increased in both models on day 5 after L-PDT; on day 1 it was significantly increased in the mesothelioma model but not in the lung cancer model.
  • Median survival was 10 days with L-PDT vs 6 days in controls for mesothelioma-bearing mice (n=5–6/group), and 47 vs 34 days for lung cancer-bearing mice (n=10/group); p<0.05.
  • E-selectin blockade prevented L-PDT-induced recruitment of CD3+/CD8+ T cells in mesothelioma mice and of CD2+ T cells in lung cancer mice.
  • When L-PDT was given with an E-selectin blocking antibody, tumor growth and survival were comparable with controls in both models.
  • In the lung cancer model, 30% of L-PDT-treated mice had metastases, compared with 90% with L-PDT plus E-selectin blocking antibody and 80% of untreated controls.
  • In mesothelioma-bearing mice only, the effect of L-PDT on tumor growth and survival was lost in T-cell-deficient nude mice and when CD8+ cells were depleted with an antibody.
  • In endothelial cells, silencing the NF-κB pathway (NEMO) abolished the L-PDT-induced rise in E-selectin: the E-selectin to GAPDH ratio was 0.98 with control siRNA vs 0.37 and 0.41 with siRNA1 or 2.
  • Among 21 patients who had surgery and chemotherapy, with matched biopsy and surgical samples, those with increased vessel E-selectin after treatment (n=13) had a median survival of 24 months, vs 8 months for decreased or stable E-selectin (n=8), p=0.0027. In epithelioid tumors the figures were 24 vs 9 months, p=0.0007.
  • Patients with CD8+ T cell infiltration above the median had a median survival of 19.5 months vs 11 months for those below the median (p=0.0056). Patients with higher or lower CD8+ infiltration after treatment did not differ in survival.
  • Among patients with CD3+/CD8+ infiltration above the median, recruited CD3/CD8 lymphocytes correlated positively with vessel E-selectin expression.
• The authors' conclusion: The authors concluded that L-PDT induced adhesion molecules on tumor blood vessels and increased immune cell infiltration in mouse mesothelioma and lung cancer, improving survival and tumor control. They stated that their preclinical results support clinical testing of L-PDT in pleural mesothelioma patients, alone or combined with other immune-stimulating treatments.
• Limitations the authors state:
  • In the matched-sample patient group, no survival analysis could be done for biphasic and sarcomatoid tumors because there were too few of these samples.

Topics

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

Medical terms in this study, explained in our Lexicon: Non-Small Cell Lung Cancer, Pleural Mesothelioma, Prognosis, Nuclear Factor kappa B (NF-κB), Immunotherapy.

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• Fluence plays a critical role on the subsequent distribution of chemotherapy and tumor growth delay in murine mesothelioma xenografts pre-treated by photodynamic therapy — Y. Wang, X. Wang, et al. (2015)
• E-cadherin, E-selectin and vascular cell adhesion molecule: immunohistochemical markers for differentiation between mesothelioma and metastatic pulmonary adenocarcinoma? — A.M. Müller, A. Weichert, et al. (2002)
• Photodynamic therapy as adjuvant therapy in surgically treated pleural malignancies — P. Baas, L. Murrer, et al. (1997)
• Surgical Inflammation Alters Immune Response to Intraoperative Photodynamic Therapy — R.W. Davis, A. Klampatsa, et al. (2023)

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