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

Abstract

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 withGpx4-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.

Recent progress in biomaterials-driven ferroptosis for cancer therapy

“…The biological activity of WA in the prodrug is further restored by excessive GSH in tumour cells, thereby inducing ferroptosis in tumour cells by combining GPX 4 inhibition and releasing catalytic reactive Fe 2+ substances through the KEAP 1-NRF 2-HMOX 1 pathway. 155,156 Ferritin lysis of tumour cells also releases a large amount of DAMP and tumour derived antigens into the wound microenvironment, which are then engulfed by antigen presenting cells (APCs) such as dendritic cells (DCs) and macrophages to trigger cross presentation and activate CTL. 157 5.2.3.…”

Ferroptosis in immunostimulation and immunosuppression

“…82 Additionally, the release of HMGB1 and oncogenic KRAS protein from ferroptotic cells can promote M2 macrophage polarization in pancreatic cancer or the recruitment and activation of myeloid-derived suppressor cells (MDSCs) in mice with Gpx4-deficient liver tumors. 83,84 Furthermore, HMGB1 can potentiate the cyclic GMP-AMP synthase (CGAS)-STING1 pathway 85 and induce the expression of immune checkpoint CD274 (also known as PD-L1) through the activation of hypoxia inducible factor 1 subunit alpha (HIF1A) transcription factor in pancreatic tumor. 86 These mechanisms contribute to the establishment of an inflammation-associated immune-suppressive tumor microenvironment.…”

Inhibition of CARM1‐Mediated Methylation of ACSL4 Promotes Ferroptosis in Colorectal Cancer

“…[11][12][13] Recent reports have shown that ferroptosis may enhance the antitumor efficacy of immunotherapies in cancer. [14,15] Therefore, an in-depth investigation of the mechanism of tumor ferroptosis and its regulation is crucial and may be of considerable aid in guiding clinical targeted therapy. Accumulation of lipid peroxidation products is a significant feature of ferroptosis and is regulated by the generation and elimination of lipid peroxides.…”