No 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.

Objective Immune checkpoint inhibition (ICI) therapy has revolutionized the outcome of certain cancers such as malignant pleural mesothelioma (MPM). However, patient responsiveness to this treatment remains unpredictable. Recently, a role for the gut microbiota composition has emerged for patients to generate a robust immune response against their tumors, following immunotherapy. Here, we studied the impact of Prembion®, a pre-biotic and modulator of the gut microbiota, on tumor control and lymphocyte infiltration in a murine MPM model treated by ICI. Methods Prembion® (diluted into drinking water) was administrated to BALBc mice for 14 days. These animals were then inoculated orthotopically with a syngeneic MPM cell line (AB12-luc cells injected in the pleura) and followed by bioluminescence imaging. We determined the tumor growth and mouse survival in different groups: untreated control, Prembion®, IgG control, anti-PDL-1, anti-CTLA4, Prembion®+anti-PDL-1 and Prembion®+anti-CTLA4. A correlation between tumor response/animal survival and MPM infiltration with CD8+ lymphocytes was also performed by immunohistochemistry. Results Prembion® was well tolerated and did not affect animal weight or activity. Interestingly, Prembion® was as effective as anti-PDL1 and anti-CTLA4 monotherapy on tumor control, prolonging survival by 4.0 ± 1.1 days compared to controls (p<0.05). Moreover Prembion® potentiated anti-CTLA4 efficacy with a significant improvement in mouse survival of the Prembion®+anti-CTLA4 compared to controls (3.6 ± 1.1 days, p<0.05). Additionally, this finding correlated with enhanced MPM infiltration by CD8+ lymphocytes compared to controls (p<0.05). Conclusion Prembion® positively regulated the adaptive immune response against MPM and helped to improve the impact of anti-CTLA4 ICI on MPM. Further work focusing on the gut microbiome changes induced by Prembion® are ongoing to better understand the mechanisms involved.