Photodynamique therapy relieves tumor vascular anergy and promotes immune cell trafficking in an orthotopic mouse model of malignant pleural mesothelioma

Abstract Objective Malignant pleural mesothelioma (MPM) is a deadly disease with limited treatment options. Recently, dual immune checkpoint inhibition therapy (ICI) showed improved patient survival. However, only a fraction of patients were responsive to immunotherapy. One potential mechanism of MPM resistance to ICIs could be their endothelial anergy that hampers leukocyte trafficking to the tumor bulk. Here, we hypothesized that vascular-targeted low dose photodynamic therapy (L-PDT), treatment of MPM could relieve tumor endothelial anergy and improve immunotherapy efficacy. Methods Using an orthotopic syngeneic MPM murine model (AB12 cells injected in the pleura of BALB/c mice), we determined the impact of L-PDT on the endothelial expression of E-Selectin, a key molecule involved in leukocyte diapedesis by immunohistochemistry. Furthermore, to confirm the role of E-selectin, we determined the extravasation of effector T cells (CD8+/CD4+) by immunostaining in L-PDT treated tumors in the presence or absence of an E-selectin blocking antibody. Finally, we assessed tumor growth/survival of our MPM murine model treated with L-PDT alone or combined to ICIs. Results L-PDT pre-treatment enhanced MPM endothelial E-Selectin expression in vivo. The latter was associated with increased CD4+ and CD8+ lymphocyte infiltration of MPM following L-PDT which did not occur after E-Selectin blockade. Also, L-PDT pre-treatment of MPM influenced favorably tumor control, mouse survival and the impact of ICIs compared to controls. Conclusion L-PDT pre-treatment relieves endothelial anergy in MPM which improves antitumor immunity and response to ICI. This approach could constitute a promising pre-treatment option, in combination with ICIs, for the management of this deadly disease.