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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.

Introduction: The management of malignant pleural mesothelioma (MPM) remains challenging with poor patient survival. Local therapies such as hyperthermic intrathoracic cisplatin (HITOC) have shown good tumor control in selected patients. HITOC was shown to increase MPM drug exposure while limiting systemic side effects but alternative mechanisms for HITOC are still lacking. Here, we hypothesized that HITOC induces an immune response directed against MPM which decreases cancer related mortality. Methods: We implanted AB12-luc MPM cells in the pleural cavity of BALB/c mice. A chemotherapy perfusion circuit was downsized to administer cisplatin (80mg/m2 equivalent dose) in the thoracic cavity at normo (37°C, ITOC) or hyperthermic (39°C, HITOC) conditions for 30 minutes. Tumor growth (visualized by bioluminescence) and mouse survival were then assessed. We determined tumor platinum content and distribution by inductively coupled plasma mass spectrometry (ICP-MS) and by laser ablation ICP-MS (LA-ICP-MS) respectively. We also questioned the impact of (H)ITOC on the MPM immune microenvironment (innate and adaptive immune cells, activity and checkpoint expression) by 16-colour flow cytometry and immunohistochemistry. Finally, tumor response to (H)ITOC was assessed in BALB/c athymic mice implanted with AB12-luc cells. Results: MPM tumor control and mouse survival were significantly improved by HITOC compared to controls (ITOC, saline 37 and 39°C). Tumor platinum content was significantly higher in HITOC compared to ITOC but was majorly located at the surface of tumors. HITOC enhanced MPM infiltration by CD8+Granzyme B+ T-cells and decreased the levels of MCHII−/CD80− (M2-like) macrophages compared to controls at day 7. Interestingly, immune checkpoint expression of PD1 and CTLA4 was significantly enhanced in CD8+ lymphocytes in HITOC treated MPM compared to controls at day 7. Finally, the lack of T lymphocytes (BALB/c athymic mice) abrogated the impact of HITOC on MPM control and mouse survival. Conclusion: HITOC improves MPM control through a T lymphocyte immune mediated response. The enhanced immune checkpoint (PD1/CTLA4) expression in CD8+ lymphocytes opens perspectives for the combination of HITOC with immune checkpoint inhibitors. Citation Format: Yameng Hao, Aspasia Gkasti, Louis-Emmanuel Chriqui, Damien Marie, Michel Gonzalez, Thorsten Krueger, Solange Peters, Paul J. Dyson, Etienne Meylan, Johanna Joyce, Sabrina Cavin, Jean Y. Perentes. Hyperthermic intrathoracic chemotherapy (HITOC) improves malignant pleural mesothelioma control through a tumor specific cytotoxic immune response. [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 6399.

BACKGROUND: Poor social health is prevalent in older adults and may be associated with worse cognition, and increased dementia risk. The aim of this study was to determine whether social isolation, social support and loneliness are independently associated with cognitive function and incident dementia over 5 years in older adults, and to investigate potential gender differences. METHODS: Participants were 11,498 community-dwelling relatively healthy Australians aged 70–94, in the ASPREE Longitudinal Study of Older Persons (ALSOP). Social isolation, social support, loneliness and cognitive function were assessed through self-report. Outcomes examined were cognitive decline (>1.5 SD decline in cognitive performance since baseline) and incident dementia (adjudicated according to DSM-IV criteria). RESULTS: Most participants self-reported good social health (92%) with very few socially isolated (2%), with low social support (2%) or lonely (5%). Among women, social isolation and low social support were consistently associated with lower cognitive function (e.g., social support and cognition β = −1.17, p < 0.001). No consistent longitudinal associations were observed between baseline social health and cognitive decline (over median 3.1 years) or incident dementia (over median 4.4 years; social isolation: HR = 1.00, p = 0.99; low social support: HR = 1.79, p = 0.11; loneliness: HR = 0.72, p = 0.34 among women and men). CONCLUSION: Our study provides evidence that social isolation and a low social support are associated with worse cognitive function in women, but not men. Social health did not predict incident cognitive decline or dementia, but we lacked power to stratify dementia analyses by gender.

Tissue organization plays an important role in tumor development and evolution. Systematic investigation of the differences in the local composition of the tumor microenvironment (TME) in glioblastoma (GBM) in distinct regions of the tumor is needed for identification of traits driving tumor recurrence. Thus, we performed an analysis of three tumors, six spatially distant biopsies each, representing tumor surface, core, and deep margin. GBM cell fluorescence generated by the 5-aminolevulinic acid (5-ALA) metabolic labeling prior to surgery allowed us to enrich for the tumor cell fractions and the cells of the microenvironment, respectively, from each biopsy. Using RNA-seq and scRNA-seq we compared the transcriptomic profiles of GBM and tumor microenvironment (TME) at distinct locations within the tumor. We observed a gradient of GBM subtypes across the tumor regions, with a molecular identity progressively less defined from the tumor core towards the margins. Interestingly, the single-cell based copy number analysis revealed a subset of GBM cells that appeared to evade the 5-ALA labelling. The high prevalence of these 5-ALA-negative GBM cells within the deep tumor margins points to a metabolically distinct subpopulation that could be responsible for local tumor recurrence. The phenotypic gradient of cancer cells from tumor core towards the margins was also mirrored by tumor microenvironment-enriched fractions. Deep margin samples from the profiled tumors were transcriptionally more divergent than biopsies from other regions. Moreover, they were depleted from major populations of TME cells. In situ analysis revealed that TERT promoter mutant cells are not equally distributed across the tumor indicating the coexistence of GBM sub-clones with distinct evolutionary potential. Altogether, our results provide a novel insight into co-evolution of tumor microenvironment and GBM clonal heterogeneity within the context of the tumor tissue.