ArticleClinical cancer research : an official journal of the American Association for Cancer Research2017
HHLA2, a New Immune Checkpoint Member of the B7 Family, Is Widely Expressed in Human Lung Cancer and Associated with EGFR Mutational Status.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 71 papers, 3 of them syntheses that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
71 citing papers in PubMed, 3 syntheses or guidelines pooled it, 100 citations in OpenAlex.
- Prognostic Value of HHLA2 in Patients with Solid Tumors: A Meta-Analysis.International journal of molecular sciences · 2024Pooled it
- Meta-analysis of global and high throughput public gene array data for robust vascular gene expression discovery in chronic rhinosinusitis: Implications in controlled release.Journal of controlled release : official journal of the Controlled Release Society · 2021Pooled it
- Phenotypical and potential functional characteristics of different immune cells expressing CD28H/B7-H5 and their relationship with cancer prognosis.Clinical and experimental immunology · 2020Pooled it
- Clinical Evaluation of HHLA2 in Hormone Receptor-Positive Breast Cancer: Expression Patterns and Prognostic Implications.Biomedicines · 2026Article
- HHLA2 as an emerging immune checkpoint in lung cancer: linking EGFR signaling, macrophage polarization, and CD8Frontiers in immunology · 2026Review
- HHLA2 activates c-Met and identifies patients for targeted therapy in hepatocellular carcinoma.Journal of experimental & clinical cancer research : CR · 2025Article
- Smoking-Associated Carcinogen-Induced Inflammation Promotes Lung Carcinogenesis via IRAK4 Activation.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
- HHLA2: a potential biomarker and therapeutic target in endocrine-related cancer.Endocrine oncology (Bristol, England) · 2025Review
- Exploring the Potential of Ellagic Acid in Gastrointestinal Cancer Prevention: Recent Advances and Future Directions.Oncology and therapy · 2024Review
- Article
- Unlocking the potential of HHLA2: identifying functional immune infiltrating cells in the tumor microenvironment and predicting clinical outcomes in laryngeal squamous cell carcinoma.Cancer immunology, immunotherapy : CII · 2024Article
- Review
- Article
- Research advances on signaling pathways regulating the polarization of tumor-associated macrophages in lung cancer microenvironment.Frontiers in immunology · 2024Review
- Regulation of HHLA2 expression in kidney cancer and myeloid cells.BMC cancer · 2023Article
- Cooperative Treatment of Gastric Cancer Using B7-H7 siRNA and Docetaxel; How Could They Modify Their Effectiveness?Advanced pharmaceutical bulletin · 2023Article
- Recent advancements in the B7/CD28 immune checkpoint families: new biology and clinical therapeutic strategies.Cellular & molecular immunology · 2023Review
- Polymorphic KIR3DL3 expression modulates tissue-resident and innate-like T cells.Science immunology · 2023Article
- Article
- KIR3DL3-HHLA2 and TMIGD2-HHLA2 pathways: The dual role of HHLA2 in immune responses and its potential therapeutic approach for cancer immunotherapy.Journal of advanced research · 2023Review
11 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
10 authors at 4 institutions in 1 country.
Funding
Abstract
purposeImmunotherapy with antibodies against B7/CD28 family members, including PD-1, PD-L1, and CTLA-4 has shifted the treatment paradigm for non-small cell lung carcinoma (NSCLC) with improved clinical outcome. HHLA2 is a newly discovered member of the family. By regulating T-cell function, HHLA2 could contribute to tumor immune suppression and thus be a novel target for cancer immunotherapy. There is limited information and critical need to characterize its expression profile and clinical significance in NSCLC. EXPERIMENTAL
designWe performed IHC with an HHLA2-specific antibody (clone 566.1) using tissue microarrays constructed from 679 NSCLC tumor tissues, including 392 cases in the discovery set and 287 cases in the validation cohort. We also studied clinicopathologic characteristics of these patients.
resultsOverall, HHLA2 was not detected in most of normal lung tissue but expressed in 66% of NSCLC across different subtypes. In particular, EGFR-mutated NSCLC was significantly associated with higher tumor HHLA2 expression in both discovery (EGFR vs. WT: 76% vs. 53%, P = 0.01) and validation cohorts (89% vs. 69%, P = 0.01). In one of the two cohorts, HHLA2 expression was higher in lung adenocarcinoma as compared with squamous and large cell histology, non-Hispanic White versus Hispanics, and tumors with high tumor-infiltrating lymphocyte (TIL) density. In the multivariate analysis, EGFR mutation status and high TIL intensity were independently associated with HHLA2 expression in lung adenocarcinoma.
conclusionsHHLA2 is widely expressed in NSCLC and is associated with EGFR mutation and high TILs in lung adenocarcinoma. It is potentially a novel target for lung cancer immunotherapy. Clin Cancer Res; 23(3); 825-32. ©2016 AACR.
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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 OpenQuestion graph.