ArticleJournal of experimental & clinical cancer research : CR2019
JAK/Stat5-mediated subtype-specific lymphocyte antigen 6 complex, locus G6D (LY6G6D) expression drives mismatch repair proficient colorectal cancer.
Article in Journal of experimental & clinical cancer research : CR, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers, 1 of them a synthesis that pooled it.
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Who cites it
29 citing papers in PubMed, 1 synthesis or guideline pooled it, 45 citations in OpenAlex.
- Tumor microenvironment-aware, single-transcriptome prediction of microsatellite instability in colorectal cancer using meta-analysis.Scientific reports · 2022Pooled it
- Trial
- Bispecific antibodies in gastrointestinal cancers: current applications and future perspectives.Frontiers in oncology · 2026Review
- Research progress of small molecule protein kinase inhibitors (SMKIs) in the treatment of colorectal cancer: mechanism, application, and future prospects.Frontiers in pharmacology · 2026Review
- Fucosylation in digestive inflammatory diseases and cancers: From mechanical studies to clinical translation.Genes & diseases · 2025Review
- Transcriptional patterns of cancer-related genes in primary and metastatic tumours revealed by machine learning.BMC biology · 2025Article
- A human and mouse subpopulation of senescent β-cells induces pathologic dysfunction through targetable paracrine signaling.bioRxiv : the preprint server for biology · 2025Article
- Does side matter? Deciphering mechanisms that underpin side-dependent pathogenesis and therapy response in colorectal cancer.Molecular cancer · 2025Review
- Article
- Ly6E on tumor cells impairs anti-tumor T-cell responses: a novel mechanism of tumor-induced immune exclusion.Cancer immunology, immunotherapy : CII · 2024Article
- Clinical and Immunologic Characteristics of Colorectal Cancer Tumors Expressing LY6G6D.International journal of molecular sciences · 2024Article
- Targeting the JAK-STAT pathway in colorectal cancer: mechanisms, clinical implications, and therapeutic potential.Frontiers in cell and developmental biology · 2024Review
- MEK Inhibition Synergizes with TYK2 Inhibitors in NF1-Associated Malignant Peripheral Nerve Sheath Tumors.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Article
- Spatially resolved transcriptomics revealed local invasion-related genes in colorectal cancer.Frontiers in oncology · 2023Article
- High-accuracy prediction of colorectal cancer chemotherapy efficacy using machine learning applied to gene expression data.Frontiers in physiology · 2023Article
- Lymphocyte antigen 6G6D-mediated modulation through p38α MAPK and DNA methylation in colorectal cancer.Cancer cell international · 2022Article
- Novel Anti-LY6G6D/CD3 T-Cell-Dependent Bispecific Antibody for the Treatment of Colorectal Cancer.Molecular cancer therapeutics · 2022Article
- LY6G6D is a selectively expressed colorectal cancer antigen that can be used for targeting a therapeutic T-cell response by a T-cell engager.Frontiers in immunology · 2022Article
- Clinical and Biological Significance of DNA Methylation-Driven Differentially Expressed Genes in Biochemical Recurrence After Radical Prostatectomy.Frontiers in genetics · 2022Article
- Identification of colon tumor marker NKD1 via integrated bioinformatics analysis and experimental validation.Cancer medicine · 2021Article
Corrections and comments
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Authors and funding
16 authors at 6 institutions in 2 countries.
Funding
Abstract
backgroundHuman microsatellite-stable (MSS) colorectal cancers (CRCs) are immunologically "cold" tumour subtypes characterized by reduced immune cytotoxicity. The molecular linkages between immune-resistance and human MSS CRC is not clear.
methodsWe used transcriptome profiling, in silico analysis, immunohistochemistry, western blot, RT-qPCR and immunofluorescence staining to characterize novel CRC immune biomarkers. The effects of selective antagonists were tested by in vitro assays of long term viability and analysis of kinase active forms using anti-phospho antibodies.
resultsWe identified the lymphocyte antigen 6 complex, locus G6D (LY6G6D) as significantly overexpressed (around 15-fold) in CRC when compared with its relatively low expression in other human solid tumours. LY6G6D up-regulation was predominant in MSS CRCs characterized by an enrichment of immune suppressive regulatory T-cells and a limited repertoire of PD-1/PD-L1 immune checkpoint receptors. Coexpression of LY6G6D and CD15 increases the risk of metastatic relapse in response to therapy. Both JAK-STAT5 and RAS-MEK-ERK cascades act in concert as key regulators of LY6G6D and Fucosyltransferase 4 (FUT4), which direct CD15-mediated immune-resistance. Momelotinib, an inhibitor of JAK1/JAK2, consistently abrogated the STAT5/LY6G6D axis in vitro, sensitizing MSS cancer cells with an intact JAK-STAT signaling, to efficiently respond to trametinib, a MEK inhibitor used in clinical setting. Notably, colon cancer cells can evade JAK2/JAK1-targeted therapy by a reversible shift of the RAS-MEK-ERK pathway activity, which explains the treatment failure of JAK1/2 inhibitors in refractory CRC.
conclusionsCombined targeting of STAT5 and MAPK pathways has superior therapeutic effects on immune resistance. In addition, the new identified LY6G6D antigen is a promising molecular target for human MSS CRC.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.