Journal Article

Combining ferroptosis induction with MDSC blockade renders primary tumours and metastases in liver sensitive to immune checkpoint blockade

Pešić, Marina, Mohs, Kathleen, Longerich, Thomas, Greten, Florian R, Dabiri, Yasamin, Ceteci, Fatih, Denk, Dominic, Finkelmeier, Fabian, Salinas, Gabriela, Engel, Esther, Conche, Claire, Kennel, Kilian B, Peiffer, Kai-Henrik, Yang, Huan, Nicolas, Adele M, Böttger, Tim W, Canli, Özge, Zeuzem, Stefan

2023

Overview

ObjectiveInvestigating the effect of ferroptosis in the tumour microenvironment to identify combinatory therapy for liver cancer treatment.DesignGlutathione peroxidase 4 (GPx4), which is considered the master regulator of ferroptosis, was genetically altered in murine models for hepatocellular carcinoma (HCC) and colorectal cancer (CRC) to analyse the effect of ferroptosis on tumour cells and the immune tumour microenvironment. The findings served as foundation for the identification of additional targets for combine therapy with ferroptotic inducer in the treatment of HCC and liver metastasis.ResultsSurprisingly, hepatocyte-restricted GPx4 loss does not suppress hepatocellular tumourigenesis. Instead, GPx4-associated ferroptotic hepatocyte death causes a tumour suppressive immune response characterised by a CXCL10-dependent infiltration of cytotoxic CD8+ T cells that is counterbalanced by PD-L1 upregulation on tumour cells as well as by a marked HMGB1-mediated myeloid derived suppressor cell (MDSC) infiltration. Blocking PD-1 or HMGB1 unleashes T cell activation and prolongs survival of mice with Gpx4-deficient liver tumours. A triple combination of the ferroptosis inducing natural compound withaferin A, the CXCR2 inhibitor SB225002 and α-PD-1 greatly improves survival of wild-type mice with liver tumours. In contrast, the same combination does not affect tumour growth of subcutaneously grown CRC organoids, while it decreases their metastatic growth in liver.ConclusionOur data highlight a context-specific ferroptosis-induced immune response that could be therapeutically exploited for the treatment of primary liver tumours and liver metastases.

• Publisher: BMJ Publishing Group Ltd and British Society of Gastroenterology,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: adenocarcinoma / Animal models / Animals / Apoptosis / Cancer therapies / Carcinoma, Hepatocellular - pathology / CD8 antigen / CD8-Positive T-Lymphocytes / Cell activation / Cell death / Cell survival / Cells / Colorectal cancer / Colorectal carcinoma / CXCL10 protein / CXCR2 protein / Cytotoxicity / Ferroptosis / Gene expression / Glutathione peroxidase / Hepatocellular carcinoma / Hepatology / HMGB1 protein / HMGB1 Protein - therapeutic use / Immune checkpoint inhibitors / Immune Checkpoint Inhibitors - pharmacology / Immune Checkpoint Inhibitors - therapeutic use / immunotherapy / Infiltration / Kinases / Lipid peroxidation / Lipids / liver / Liver cancer / Liver Neoplasms - pathology / Lymphocytes / Lymphocytes T / Metastases / Metastasis / Mice / Microenvironments / Myeloid-Derived Suppressor Cells / Organoids / PD-1 protein / PD-L1 protein / Programmed Cell Death 1 Receptor / Tumor Microenvironment / Tumorigenesis / Tumors / Vitamin E