Hyperthermic Intrathoracic Chemotherapy (HITOC) Improves Malignant Pleural Mesothelioma Control Through a Tumor Specific Cytotoxic Immune Response

Abstract

Abstract Background 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. Aims We hypothesized that HITOC induces an immune response directed against MPM which decreases cancer related mortality. Methods A perfusion circuit was downsized to administer cisplatin in the thoracic cavity of MPM bearing mice at normo (37°C, ITOC) or hyperthermic (39°C, HITOC) conditions for 30 minutes. Tumor platinum content and distribution were determined by inductively coupled plasma mass spectrometry (ICP-MS) and by laser ablation ICP-MS respectively. The impact of (H)ITOC on the MPM immune microenvironment was questioned using flow cytometry and immunohistochemistry. Tumor growth and survival was assessed in immunocompetent and T-cell deficient mice. Finally, the combination of HITOC with anti-CTLA-4 and anti-PD-1 antibodies was evaluated in immunocompetent animals. Results MPM tumor control and mouse survival were significantly improved by HITOC compared to controls (ITOC, saline 37 and 39°C). This correlated with higher tumor platinum content that was mainly located at the surface of tumors. Furthermore, HITOC enhanced MPM infiltration by cytotoxic T-cells and decreased the level of protumor (M2-like) macrophages at day 7. The beneficial impact of HITOC on tumor control and mice survival was lost in immunocompromised animals. Interestingly, HITOC significantly induced PD-1 and CTLA-4 immune checkpoint molecules expression and administration of dual immune checkpoint blockade after HITOC increased of almost two fold the median survival of the animals. Conclusions HITOC improves MPM control through a T lymphocyte immune mediated response. The potentiation of the immune checkpoint blockade response by HITOC opens new perspectives for the combination of immune checkpoint inhibitors with HITOC in clinic.