Abstract
Multimodal therapy for peritoneal metastasis (PM) including cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) provides long-term survival in highly selected colorectal cancer patients. Mechanisms behind HIPEC are unknown and may include induction of adaptive immunity. We therefore analyzed human PM samples and explored the impact of HIPEC in experimental models. Human samples from colorectal primary tumors (n = 19) and PM lesions (n = 37) were examined for the presence of CD8 + T-cells and their association with disease free (DFS) and overall survival (OS). CD8 + T cell response after HIPEC was assessed using an in-vivo PM mouse model, tumor cell lines and patient-derived tumor organoids. Patients with high intraepithelial CD8 + T cell counts showed longer DFS and OS. In the mouse model, HIPEC controlled growth of PM and increased numbers of functional granzyme positive CD8 + T cells within tumors. Cell lines and human organoids that were treated with heated chemotherapies showed immunogenic changes, reflected by significantly higher levels of MHC-class I molecules and expression of Cancer Testis Antigens Cyclin A1 and SSX-4. Using in-vitro co-culture assays, we noticed that cancer cells treated with heated chemotherapy primed dendritic cells, which subsequently enhanced effector functions of CD8 + T cells. The presence of CD8 + T-cells within PM lesions is associated with prolonged survival of patients with PM. Data from PM mouse model and in-vitro assay show that heated chemotherapies induce immunogenic changes on cancer cells leading to induction of CD8 + T-cells mediated immunity, which seems to control growth of PM lesions in mice after HIPEC.