A PRRX1 Signature Identifies TIM-3 and VISTA as Potential Immune Checkpoint Targets in a Subgroup of Microsatellite Stable Colorectal Cancer Liver Metastases.

Autor:	Nygaard V; Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway., Ree AH; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.; Department of Oncology, Akershus University Hospital, Lørenskog, Norway., Dagenborg VJ; Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.; Department of Gastroenterological Surgery, Oslo University Hospital, Oslo, Norway., Børresen-Dale AL; Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway., Edwin B; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.; Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway.; The Intervention Center, Oslo University Hospital, Oslo, Norway., Fretland ÅA; Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway.; The Intervention Center, Oslo University Hospital, Oslo, Norway., Grzyb K; Department of Pathology, Oslo University Hospital, Oslo, Norway., Haugen MH; Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway., Mælandsmo GM; Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; Institute for Medical Biology, Faculty of Health Sciences, UiT-The Arctic University of Norway, Tromsø, Norway., Flatmark K; Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.; Department of Gastroenterological Surgery, Oslo University Hospital, Oslo, Norway.
Jazyk:	angličtina
Zdroj:	Cancer research communications [Cancer Res Commun] 2023 Feb 09; Vol. 3 (2), pp. 235-244. Date of Electronic Publication: 2023 Feb 09 (Print Publication: 2023).
DOI:	10.1158/2767-9764.CRC-22-0295
Abstrakt:	Disease recurrence and drug resistance are major challenges in the clinical management of patients with colorectal cancer liver metastases (CLM), and because tumors are generally microsatellite stable (MSS), responses to immune therapies are poor. The mesenchymal phenotype is overrepresented in treatment-resistant cancers and is associated with an immunosuppressed microenvironment. The aim of this work was to molecularly identify and characterize a mesenchymal subgroup of MSS CLM to identify novel therapeutic approaches. We here generated a mesenchymal gene expression signature by analysis of resection specimens from 38 patients with CLM using ranked expression level of the epithelial-to-mesenchymal transition-related transcription factor PRRX1 . Downstream pathway analysis based on the resulting gene signature was performed and independent, publicly available datasets were used to validate the findings. A subgroup comprising 16% of the analyzed CLM samples were classified as mesenchymal, or belonging to the PRRX1 high group. Analysis of the PRRX1 signature genes revealed a distinct immunosuppressive phenotype with high expression of immune checkpoints HAVCR2/TIM-3 and VISTA, in addition to the M2 macrophage marker CD163. The findings were convincingly validated in datasets from three external CLM cohorts. Upregulation of immune checkpoints HAVCR2/TIM-3 and VISTA in the PRRX1 high subgroup is a novel finding, and suggests immune evasion beyond the PD-1/PD-L1 axis, which may contribute to poor response to PD-1/PD-L1-directed immune therapy in MSS colorectal cancer. Importantly, these checkpoints represent potential novel opportunities for immune-based therapy approaches in a subset of MSS CLM. Significance: CLM is an important cause of colorectal cancer mortality where the majority of patients have yet to benefit from immunotherapies. In this study of gene expression profiling analyses, we uncovered novel immune checkpoint targets in a subgroup of patients with MSS CLMs harboring a mesenchymal phenotype. Competing Interests: V. Nygaard reports grants from Research Council of Norway, South-Eastern Norway Health Authority, and Sister Institution Network Fund during the conduct of the study. Å.A. Fretland reports personal fees from Bayer and Olympus outside the submitted work. M.H. Haugen reports grants from South-Eastern Healt Authorities Norway and MD Anderson Sister Institution Network Fund (SINF) during the conduct of the study. No disclosures were reported by the other authors. (© 2023 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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