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OBJECTIVE: Malignant pleural mesothelioma (MPM) is a rare disease that has a poor response to conventional therapy. Hyperthermic intrathoracic chemotherapy (HITOC), a treatment combining fever-range hyperthermia with intrapleural cisplatin chemotherapy, has been used following MPM surgery to improve MPM control and patient survival. However, the precise mechanisms involved in HITOC control of MPM were lacking, mostly because no animal model was available to date. In this thesis, we hypothesized that HITOC could significantly modulate the tumor immune microenvironment and improve immune related control of MPM, an effect that could be further enhanced by the combination of HITOC with immune checkpoint inhibitors (ICIs). METHODS: We developed a novel and unique orthotopic MPM mouse model where HITOC could be applied and studied. For this, mesothelioma AB12 cells transfected with a luciferase construct were orthotopically implanted in BALB/c mice and tumor growth was monitored following luciferin injection by bioluminescence imaging. We then downsized the HITOC clinical system to our mouse model and developed a surgical procedure allowing HITOC treatment and animal survival. We assessed cisplatin distribution within tumor by Inductively Coupled Plasma Mass Spectrometry (ICP-MS) and Laser Ablation ICP-MS (LA-ICP-MS). We determined the impact of HITOC on the tumor immune microenvironment by 15-color flow cytometry and immunohistochemistry. We also assessed tumor growth and mouse survival with HITOC in the presence or absence of anti-PD-1/CTLA-4 antibodies. Finally, we assessed the CD8+ T cell infiltration in patient mesothelioma samples exposed to normothermic pressurized cisplatin local therapy. RESULTS: In this thesis we showed, for the first time, that HITOC can be studied in vivo with a reliable MPM murine model and significantly improved tumor control and animal survival. In addition, we showed that the impact of HITOC on tumor cisplatin uptake as opposed to non-hyperthermic conditions was marginal. However, we reported significant changes in the tumor immune microenvironment compositions following HITOC, with increased CD45+ leukocytes infiltration, MHC-II expression on CD11b+ dendritic cells, as well as the infiltration of B cells, CD4+ and CD8+ T cells compared to normothermic intrathoracic saline (NITOS) at day 7 post treatment. We also found a significant change of macrophage polarization toward M1-like phenotype (MHC-II+ CD80+) by flow cytometry analyses. Using the same MPM model in athymic BALB/c mice (that has an absence of functional T cells), we showed that the survival and tumor control advantage of HITOC was lost. We also found that HITOC increased the amount of PD-1+ and CTLA-4+ CD8+ T cells in the tumor area, and the combination of HITOC with anti-PD-1/CTLA-4 antibodies showed the best animal survival. Finally, we showed that patient mesothelioma samples exposed to local cisplatin chemotherapy had, over treatment cycles, a significant increase in their CD8+ T lymphocyte content. CONCLUSIONS: To our knowledge, this is the first study showing an immune impact of HITOC in the context of MPM. We provide mechanistic insight on the role of CD8+ T lymphocytes as well as a rationale for combining HITOC with ICIs. Finally, the increase of CD8+ T cells for mesothelioma control following local cisplatin chemotherapy is validated in patient samples suggesting future perspectives for HITOC combination with ICIs in patients.
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