HHLA2 deficiency inhibits non‐small cell lung cancer progression and THP‐1 macrophage M2 polarization

Sun, Wenjie; Li, Shuying; Tang, Guiliang; Sun, Shaoxing; Luo, Yuan; Bai, Rui; Jiang, Xueping; Gao, Yanping; Huang, Zhengrong; Zhang, Mengjie; Gong, Yan; Xie, Conghua

doi:10.1002/cam4.4081

Cited by 30 publications

(27 citation statements)

References 43 publications

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“…Previous studies have discovered that HHLA2 is overexpressed in gastric cancer, osteosarcoma, clear cell renal cell carcinoma, bladder urothelial cancer, and HCC and is associated with a poor prognosis ( 8 – 11 ). High HHLA2 overexpression in cancer tissues has been linked to cancer development and malignant characteristics, whereas HHLA2 deficiency inhibits NSCLC cell proliferation, migration, and M2 macrophage polarization ( 12 ). However, HHLA2’s biological functions in liver cancer are yet to be closely examined.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Analysis of HHLA2 as a Prognostic Biomarker and Its Association With Immune Infiltrates in Hepatocellular Carcinoma

Ding

Yang

et al. 2022

Front. Immunol.

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BackgroundInhibitory immune checkpoint proteins promote tumor immune escape and are associated with inferior patient outcome. However, the biological functions and regulatory roles of one of its members, HHLA2, in the tumor immune microenvironment have not been explored.MethodsRandomForest analyses (371 cases), qRT-PCR (15 cases), and immunohistochemical staining (189 cases) were used to validate the prognostic value of HHLA2 in hepatocellular carcinoma (HCC) patients. Bioinformatic analyses were further performed to explore the biological functions and potential signaling pathways affected by HHLA2. Moreover, ESTIMATE, single sample gene set enrichment analysis, CIBERSORT, TIMER, and other deconvolution methods were used to analyze the composition and infiltration level of immune cells. Multiplex immunofluorescence assays were employed to validate the fractions of suppressive immune cells, and HHLA2-related molecular alterations were investigated. Finally, the clinical response to chemotherapy and immune checkpoint blockade was predicted by TIDE, Submap, and several other in silico analyses.ResultsRandomForest analysis revealed that HHLA2 was the most important inhibitory immune checkpoint associated with HCC patient prognosis (relative importance = 1). Our HCC cohorts further revealed that high HHLA2 expression was an independent prognostic biomarker of shorter overall survival (P<0.01) and time to recurrence (P<0.001) for HCC patients. Bioinformatics experiments revealed that HHLA2 may accelerate the cell cycle of cancer cells. Additionally, we found that high expression of HHLA2 was associated with immune infiltrates, including some immunosuppressive cells, cytokines, chemokines, and corresponding receptors, resulting in an immunosuppressive environment. Notably, HHLA2 expression was positively correlated with the infiltration of exhausted CD8+ T cells, which was validated by immunofluorescence. Genomic alteration analyses revealed that promoter hypermethylation of HHLA2 may be associated with its low expression. More importantly, patients with high HHLA2 expression may be more sensitive to chemotherapy and have better responses to immunotherapy.ConclusionsHigh expression of HHLA2 is an independent prognostic biomarker for HCC patients. It can activate the cell cycle and foster an immunosuppressive tumor microenvironment by enriching exhausted CD8+ T cells. Promoter hypermethylation might lead to low expression of HHLA2 in HCC. Thus, targeting HHLA2 may be a practical therapeutic strategy for HCC patients in the future.

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Section: Introductionmentioning

confidence: 99%

Comprehensive Analysis of HHLA2 as a Prognostic Biomarker and Its Association With Immune Infiltrates in Hepatocellular Carcinoma

Ding

Yang

et al. 2022

Front. Immunol.

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“…Janakiram et al [ 9 ] demonstrated that HHLA2 is widely expressed in a large proportion of cancer samples such as breast cancer, colon cancer, and prostate cancer. In recent years, studies have shown that HHLA2 participates in the growth and development of a variety of cancers [ 7 , 10 , 11 ]. However, to date, the expression pattern, prognostic significance, and biological function of HHLA2 in cancer have not been elucidated fully.…”

Section: Introductionmentioning

confidence: 99%

[Retracted] HHLA2 Used as a Potential Prognostic and Immunological Biomarker and Correlated with Tumor Microenvironment in Pan‐Cancer

Yang

et al. 2022

BioMed Research International

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Background. The role of HERV–H LTR-associating 2 (HHLA2) in cancer remains still unclear. This study analyzed the correlation between the prognosis and immune infiltrate function of HHLA2 in pan-cancers. Methods. HHLA2 expression in pan-cancers was analyzed using the databases of TCGA, GTEx, TIMER, GEPIA, UALCAN, and GSEA databases. Multiple bioinformatic methods were used to investigate the correlation of HHLA2 expression with survival, pathological stage, tumor mutation burden (TMB), microsatellite instability (MSI), tumor microenvironment (TME), immune cell infiltration, and immune checkpoint gene (ICG), and gene functional enrichment was performed by Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA). Results. HHLA2 was aberrantly expressed and was strongly correlated with positive or negative prognosis in multiple human cancers, which revealed that HHLA2 might play a vital role during cancer formation and development. Kaplan–Meier (KM) curves across cancers revealed that HHLA2 expression was correlated with overall survival (OS) in eight cancers, disease-specific survival (DSS) in seven cancers, disease-free interval (DFI) in four cancers, and progression-free interval (PFI) in nine cancers. Furthermore, HHLA2 expression was positively correlated with TMB in 6 cancer types and negatively associated with TMB in 7 cancer types, respectively. The former included ESCA, HNSC, KIRP, PAAD, PRAD, and PCPG; the latter contained COAD, LGG, LUAD, LUSC, THYM, THCA, and UCEC. Additionally, we found HHLA2 expression was negatively related to MSI in ACC, COAD, PAAD, and UCEC. More importantly, HHLA2 expression was remarkably correlated with the degree of tumor-infiltrating immune in many cancers, including B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells and strongly associated with immune checkpoint genes in 13 tumor types. Furthermore, KEGG pathway analyses indicated that HHLA2 could potentially impact cancer etiology or pathogenesis by functioning in amino sugar and nucleotide sugar metabolism, cytosolic DNA sensing pathway, and peroxisome pathways. Meanwhile, GSVA analysis results all indicate that HHLA2 was correlated with TSC/mTOR, RTK, RAS/MAPK, PI3K/AKT, EMT, DNA Damage Response, Cell Cycle, and Apoptosis pathways in various cancers. Conclusion. HHLA2 can function as a prognostic biomarker and correlate with tumor immunity in human pan-cancer due to its important role in tumorigenesis and immune infiltration, which provides new insight into developing new targeted treatments in cancers.

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“…In NSCLC, the EGFR/MAPK/ERK signaling pathway was demonstrated to be the mechanism, through which HHLA2 regulated cell proliferation, migration, invasion, and cell cycle. 23 The function of HHLA2 in immune processes has been widely reported, and numerous studies have focused on the role of immune regulation and immune escape in PTC. For example, a previous study identified a variety of dysregulated immune-related genes in PTC and established a risk model predicting the clinical outcome.…”

Section: Discussionmentioning

confidence: 99%

Human Endogenous Retrovirus-H Long Terminal Repeat-Associating Protein 2 Possesses Prognostic Significance and Promotes Progression of Papillary Thyroid Cancer

Niu¹,

Huang²,

Dong³

et al. 2022

IJGM

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Identification of novel biomarkers could benefit the clinical therapy and management of papillary thyroid carcinoma (PTC). Human endogenous retrovirus long terminal repeat-associating protein 2 (HHLA2) has been reported to play roles in the development of various cancers. The clinical significance and biological function of HHLA2 in PTC were investigated. Patients and Methods:The expression level of HHLA2 was evaluated in PTC tissues (from 107 PTC patients) and cell lines (TPC-1, IHH-4, CGTH-W3, and MDA-T32 cells) by RT-qPCR. The clinical significance of HHLA2 was estimated with a series of statistical analyses. The biological function of HHLA2 was assessed with the CCK8 assay and transwell assay. Results: HHLA2 was upregulated in PTC compared with the normal samples and was associated with the positive lymph node metastasis and advanced TNM stage of PTC patients. HHLA2 was an independent prognostic factor associated with the poor survival of PTC patients. Additionally, HHLA2 functioned as a tumor promoter that enhanced the progression of PTC cells. Conclusion: HHLA2 could serve as a prognostic biomarker and tumor promoter in PTC, providing a novel therapeutic target of PTC.

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HHLA2 deficiency inhibits non‐small cell lung cancer progression and THP‐1 macrophage M2 polarization

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 30 publications

References 43 publications

Comprehensive Analysis of HHLA2 as a Prognostic Biomarker and Its Association With Immune Infiltrates in Hepatocellular Carcinoma

Comprehensive Analysis of HHLA2 as a Prognostic Biomarker and Its Association With Immune Infiltrates in Hepatocellular Carcinoma

[Retracted] HHLA2 Used as a Potential Prognostic and Immunological Biomarker and Correlated with Tumor Microenvironment in Pan‐Cancer

Human Endogenous Retrovirus-H Long Terminal Repeat-Associating Protein 2 Possesses Prognostic Significance and Promotes Progression of Papillary Thyroid Cancer

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