Hyperthermic Intrathoracic Chemotherapy Modulates the Immune Microenvironment of Pleural Mesothelioma and Improves the Impact of Dual Immune Checkpoint Inhibition

Abstract

Pleural mesothelioma is a fatal disease with limited treatment options. Recently, pleural mesothelioma management has improved with the development of immune checkpoint inhibitors (ICI). In first-line therapy, dual PD-1 and CTLA-4 blockade enhances tumor control and patient survival compared with chemotherapy. Unfortunately, only a fraction of patients is responsive to immunotherapy, and approaches to reshape the tumor immune microenvironment and make ICIs more effective are urgently required. In this study, we evaluated the effect of hyperthermic intrathoracic chemotherapy (HITOC), a treatment that combines fever-range hyperthermia with local intrapleural cisplatin chemotherapy, on the tumor immune microenvironment and response to ICIs. To do this, we developed a murine pleural mesothelioma model of HITOC. We found that HITOC significantly improved tumor control and animal survival through a mechanism involving the development of a cytotoxic immune response. Additionally, HITOC enhanced immune checkpoint expression by T lymphocytes and synergized with dual PD-1 and CTLA-4 inhibition, leading to further improvement in animal survival. Finally, the analysis of peritoneal mesothelioma patient samples treated by pressurized intraperitoneal aerosol chemotherapy revealed a similar immunomodulation. In conclusion, HITOC remodels the tumor immune microenvironment of pleural mesothelioma by promoting T-cell infiltration into the tumor and could be considered in combination with ICIs in the context of a clinical trial.