TY  - JOUR
AU  - Conche, Claire
AU  - Finkelmeier, Fabian
AU  - Pešić, Marina
AU  - Nicolas, Adele M
AU  - Böttger, Tim W
AU  - Kennel, Kilian B
AU  - Denk, Dominic
AU  - Ceteci, Fatih
AU  - Mohs, Kathleen
AU  - Engel, Esther
AU  - Canli, Özge
AU  - Dabiri, Yasamin
AU  - Peiffer, Kai-Henrik
AU  - Zeuzem, Stefan
AU  - Salinas, Gabriela
AU  - Longerich, Thomas
AU  - Yang, Huan
AU  - Greten, Florian R
TI  - Combining ferroptosis induction with MDSC blockade renders primary tumours and metastases in liver sensitive to immune checkpoint blockade.
JO  - Gut
VL  - 72
IS  - 9
SN  - 0017-5749
CY  - London
PB  - BMJ Publishing Group
M1  - DKFZ-2023-00221
SP  - 1774-1782
PY  - 2023
N1  - 2023 Sep;72(9):1774-1782
AB  - Investigating the effect of ferroptosis in the tumour microenvironment to identify combinatory therapy for liver cancer treatment.Glutathione 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.Surprisingly, 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.Our data highlight a context-specific ferroptosis-induced immune response that could be therapeutically exploited for the treatment of primary liver tumours and liver metastases.
KW  - adenocarcinoma (Other)
KW  - cell death (Other)
KW  - colorectal cancer (Other)
KW  - immunotherapy (Other)
KW  - liver (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:36707233
DO  - DOI:10.1136/gutjnl-2022-327909
UR  - https://inrepo02.dkfz.de/record/212536
ER  -