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Introduction: Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited treatment options. The application of photodynamic therapy (PDT) was shown to significantly improve patient survival. Previously, we found that low dose PDT (L-PDT) enhanced the immune infiltration of MPM and increased the impact of immune checkpoint inhibitors on tumor control. However, the mechanisms behind these observations are unknown. Here, in an orthotopic murine model of MPM, we show that L-PDT upregulates tumor vascular E-Selectin expression via NF-kB. This upregulation favors enhanced leukocyte trafficking and immune mediated MPM regression. Methods: We analyzed adhesion molecules (E-Selectin, ICAM-1, VCAM-1) and canonical NF-kB activation (phosphorylated IκBα) protein levels in endothelial (ECRF-24) cells treated by L-PDT in the presence or absence of a NEMO/IKKγ siRNA in vitro. For in vivo validation, AB12-Luc MPM cells were grown in the pleural cavity of syngeneic BALB/c mice and treated with L-PDT (verteporfin 400 µg/kg, fluence 10 J/cm2, fluence rate 50 mW/cm2) alone or in presence of NF-kB or E-Selectin inhibitors (NEMO Binding Domain (NBD) peptide and E-Selectin blocking antibody respectively). For each treatment group, we determined the expression of endothelial adhesion molecules (E-Selectin, ICAM-1, VCAM-1) and the tumor immune infiltrate by immunohistochemistry and flow cytometry. In parallel, the impact of L-PDT on MPM growth and mouse survival were assessed in the presence of E-Selectin inhibition. Results: L-PDT increased the levels of endothelial adhesion molecules E-Selectin, ICAM-1 and VCAM-1 9 to 24 hours after L-PDT treatment in vitro. This was preceded by an increase of IκBα phosphorylation. In the presence of NEMO siRNAs, the expression of NEMO/IKKγ was reduced and led to E-Selectin repression. In orthotopic MPM bearing mice, the treatment of MPM by L-PDT enhanced adhesion molecules expression in tumor vasculature at 24 hours. This correlated with increased infiltration of CD4+ and CD8+ granzyme B+ T-cells and improved tumor control and mouse survival. NF-kB inhibition impaired tumor vascular adhesion molecules upregulation and the recruitment of tumor infiltrating lymphocytes in MPM. The targeted inhibition of E-Selectin abrogated the immune infiltration and tumor regression of MPM following L-PDT, which ultimately decreased animal survival in our MPM model. Conclusion: Low dose PDT relieves MPM tumor vascular anergy via NF-kB mediated adhesion molecules expression. Endothelial E-Selectin has been identified, in our MPM model, as a major determinant for L-PDT enhanced lymphocyte trafficking, tumor control and animal survival. Citation Format: Louis-Emmanuel Chriqui, Yameng Hao, Damien Marie, Michel Gonzalez, Thorsten Krueger, Etienne Meylan, Johanna Joyce, Sabrina Cavin, Jean-Yannis Perentes. Photodynamic therapy promotes immune infiltration and control of malignant pleural mesothelioma through NF-kB mediated upregulation of E-Selectin in the tumor vasculature. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5152. |
