B cell lymphoma 6 promotes hepatocellular carcinoma progression by inhibiting tumor infiltrating CD4+T cell cytotoxicity through ESM1

Immunotherapy exhibited potential effects for advanced hepatocellular carcinoma, unfortunately, the clinical benefits are often countered by cancer adaptive immune suppressive response. Uncovering the mechanism how cancer cells evade immune surveillance would help to develop new immunotherapy approa...

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Published in:NPJ precision oncology 2024-07, Vol.8 (1), p.139-16, Article 139
Main Authors: Li, Jiatao, Feng, Juan, Li, Ziyong, Ni, Yuanli, Liu, Limei, Lei, Xia, Chai, Zixuan, Zhuang, Na, Xu, Jiake, He, Yongpeng, Shan, Juanjuan, Qian, Cheng
Format: Article
Language:English
Subjects:
631/67/580/1884
692/4028/67/395
Antigens
Cancer Research
Cancer therapies
Cell death
Clinical outcomes
Cytokines
Cytotoxicity
DNA repair
Gene Therapy
Genomes
Human Genetics
Immunotherapy
Internal Medicine
Leukemia
Liver cancer
Lymphocytes
Lymphoma
Medicine
Medicine & Public Health
Oncology
Patients
Proteins
Transcription factors
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Summary:Immunotherapy exhibited potential effects for advanced hepatocellular carcinoma, unfortunately, the clinical benefits are often countered by cancer adaptive immune suppressive response. Uncovering the mechanism how cancer cells evade immune surveillance would help to develop new immunotherapy approaches and combination therapy. In this article, by analyzing the transcriptional factors which modulate the differentially expressed genes between T cell infiltration high group and low group, we identified oncoprotein B cell lymphoma 6 (BCL6) suppresses the infiltration and activation of tumor infiltrating T lymphocytes, thus correlated with poorer clinical outcome. By using antibody deletion experiment, we further demonstrated that CD4 + T cells but not CD8 + T cells are the main lymphocyte population suppressed by Bcl6 to promote HCC development. Mechanistically, BCL6 decreases cancer cell expression of pro-inflammatory cytokines and T lymphocyte chemokines such as IL6, IL1F6, and CCL5. Moreover, BCL6 upregulates Endothelial cell-specific molecule 1 (ESM1) to inhibit T lymphocyte recruitment and activation possibly through ICAM-1/LFA-1 signaling pathway. Our findings uncovered an unappreciated paracrine mechanism how cancer cell-derived BCL6 assists cancer cell immune evasion, and highlighted the role of CD4 + T cells in HCC immune surveillance.
ISSN:2397-768X
2397-768X
DOI:10.1038/s41698-024-00625-7