Activation of Adaptive Immune Cells is an Early Response to Hyperthermic Intraperitoneal Chemotherapy Treatment in Ovarian Cancer

Abstract

\n Hyperthermic intraperitoneal chemotherapy (HIPEC) has significantly increased the survival of epithelial ovarian (EOC) patients and is being adopted as a standard clinical approach for managing these tumors. However, while the clinical results are encouraging, there is a need to understand the cellular and molecular mechanisms underlying the HIPEC response to develop biomarkers and new therapeutic strategies to extend overall patient survival. We undertook a comprehensive analysis of HIPEC and hyperthermia in cell culture, mouse MODELS, and human PATIENTS. Ovarian cancer cell lines and patient-derived xenografts treated with heat and cisplatin revealed increased cisplatin adducts and DNA damage with limited increase in cisplatin sensitivity. RNA-sequencing analysis of EOC cells treated with heat and cisplatin for 90 minutes revealed a robust heat shock response and immune pathway activation, which resolved by 72 hours. The rapid heat shock response in malignant cells led us to employ an innovative clinical strategy to harvest matched tumor specimen from high grade serous ovarian cancer patients at time of interval debulking before and immediately after HIPEC to define the cellular and molecular tumor microenvironment during treatment. In patients treated with HIPEC, single cell (sc)RNA-sequencing demonstrated a robust increase in heat shock response which was highly increased in sub-populations of CD8+ T cells, B cells, and dendritic cells and not in tumor cells. Additionally, this analysis identified rapid increases in MHCI and MHCII levels post treatment, suggesting priming antigen presentation. Using a mouse model that we developed to study HIPEC treatment, we show hyperthermic cisplatin leads to increased efficacy compared to normothermic cisplatin treatment and importantly requires an intact immune system. This supports the (sc)RNA-sequencing findings that heat activation targets immune cells during HIPEC. Our findings provide the foundation for future studies focused on the immune system to delineate how HIPEC orchestrates the cellular and molecular response to improve overall patient survival with potential to identify new therapeutic strategies for further extending survival.