B7-H7 (HHLA2) inhibits T-cell activation and proliferation in the presence of TCR and CD28 signaling

Rieder, Sadiye Amcaoglu; Wang, Jingya; White, Neil W.; Qadri, Ariful N.; Ménard, Catherine; Stephens, Geoffrey L.; Karnell, Jodi L.; Rudd, Christopher E.; Kolbeck, Roland

doi:10.1038/s41423-020-0361-7

Cited by 51 publications

(33 citation statements)

References 30 publications

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“…In our experiments, HHLA2 knockdown enhanced the adhesion between HepG2 cells and the extracellular matrix in vitro. Our results are consistent with a transcriptome study [ 19 ], indicating that HHLA2 is involved in regulating intercellular adhesion between primary human T cells and the extracellular matrix. In fact, the less adhesive the tumor, the more effectively it evades immune killing, which is proposed by the “tumor growth-cell immune feedback” model.…”

Section: Discussionsupporting

confidence: 93%

H Long Terminal Repeat-Associating 2 (HHLA2) is a Biomarker of Advanced Stage Hepatocellular Carcinoma and Promotes Tumor Cell Development In Vitro

et al. 2021

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Background Several risk factors contribute to the inflammation promoting hepatocellular carcinoma (HCC) development, but the underlying mechanisms are unknown. Human endogenous retrovirus H long terminal repeat-associating 2 (HHLA2), a B7 family member, is highly expressed in various malignant tumor tissues and is related to tumor progression and metastasis. Material/Methods Bioinformatics analysis was used to analyze the gene expression chip GSE33006 of HCC tissue in the GEO database, draw a heat map of differentially expressed genes, and analyze the GO pathway of gene function annotation. Then, we compared HCC tissues with para-carcinoma liver tissues from 55 patients for expression patterns and associations with HHLA2. Effects of HHLA2 knockdown were examined in the human HCC cell line HepG2 to explore effects of HHLA2 on HepG2 cells. Results A significantly higher expression of HHLA2 at the mRNA and protein levels was detected in HCC tissues than in para-carcinoma liver tissues, which was similar to HHLA2 expression in the GSE33006 data. A higher expression of HHLA2 protein was associated with advanced cancer stage, tumor differentiation, and invasion of adjacent structures. In vitro knockdown of HHLA2 expression significantly increased HepG2 cell adhesion, promoted cell apoptosis, induced cell cycle arrest in the G1/S phase, and inhibited cell proliferation, migration, and invasion. Conclusions Our data indicated there was a higher expression of HHLA2 in HCC tissues than in para-carcinoma liver tissues, and HHLA2 plays a major role in the development and progression of HCC. Owing to its higher expression, HHLA2 is a potential prognostic biomarker for HCC.

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Section: Discussionsupporting

confidence: 93%

H Long Terminal Repeat-Associating 2 (HHLA2) is a Biomarker of Advanced Stage Hepatocellular Carcinoma and Promotes Tumor Cell Development In Vitro

et al. 2021

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“…In analogy to B7.1 and B7.2 that ligate CTLA-4 and CD28 to inhibit and stimulate T cell responses respectively, B7-H7 has been shown to ligate KIR3DL3 and CD28H to inhibit and stimulate T cell responses respectively (14). However, Rieder et al showed that the inhibitory effect of B7-H7 signalling is evident as early as 24 h after the initial stimulation (11). Nevertheless, KIR3DL3 is not expressed on resting T cells and the expression is less than 5% upon cross-linking CD3 and CD28 (14).…”

Section: Discussionmentioning

confidence: 99%

“…Zhao et al reported that B7-H7 inhibit T cells proliferation and cytokine secretion (2), while Zhu et al demonstrated that B7-H7 co-stimulates T cells via its receptor CD28H (4). Following these initial report, more recent studies have also reported both inhibitory and stimulatory functions of B7-H7 (11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

B7-H7 Is Inducible on T Cells to Regulate Their Immune Response and Serves as a Marker for Exhaustion

2021

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The discovery of immune checkpoints highlights the complexity of T cell signalling during an immune response. Upon activation, T cells express several molecules to regulate their function and to prevent overactivation. B7 homolog 7 (B7-H7) is expressed in tumours and associated with a worse prognosis. However, conflicting data regarding its function suggest that it can be both stimulatory and inhibitory. In this study we report that B7-H7 is also expressed on T cells upon cross-linking of CD3 and CD28 and that additional stimulation via CD137 further enhances the expression of B7-H7. B7-H7 is preferentially expressed on exhausted Th1 and Tc1 cells with an impaired secretion of TNF-α and IFN-γ. Blockade of B7-H7 with its natural receptor, recombinant CD28H, enhances T cell proliferation and activation. Thus, B7-H7 represents another target for immunotherapy and a biomarker to select for active effector T cells with relevance for adoptive cell transfer therapy.

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“…HHLA2, a member of the B7 family, can predict poor overall survival in several cancers, including human clear cell renal cell carcinoma and colorectal carcinoma [125]. HHLA2 can suppress T-cell activation and proliferation in the presence of TCR and CD28 signaling [126], and can do this more robustly than PD-L1 [127].…”

Section: Hhla2mentioning

confidence: 99%

Recent Advancements in the Mechanisms Underlying Resistance to PD-1/PD-L1 Blockade Immunotherapy

Yuan

Adam

Zhao

et al. 2021

Cancers

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Release of immunoreactive negative regulatory factors such as immune checkpoint limits antitumor responses. PD-L1 as a significant immunosuppressive factor has been involved in resistance to therapies such as chemotherapy and target therapy in various cancers. Via interacting with PD-1, PD-L1 can regulate other factors or lead to immune evasion of cancer cells. Besides, immune checkpoint blockade targeting PD-1/PD-L1 has promising therapeutic efficacy in the different tumors, but a significant percentage of patients cannot benefit from this therapy due to primary and acquired resistance during treatment. In this review, we described the utility of PD-L1 expression levels for predicting poor prognosis in some tumors and present evidence for a role of PD-L1 in resistance to therapies through PD-1/PD-L1 pathway and other correlating signaling pathways. Afterwards, we elaborate the key mechanisms underlying resistance to PD-1/PD-L1 blockade in cancer immunotherapy. Furthermore, promising combination of therapeutic strategies for patients resistant to PD-1/PD-L1 blockade therapy or other therapies associated with PD-L1 expression was also summarized.

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B7-H7 (HHLA2) inhibits T-cell activation and proliferation in the presence of TCR and CD28 signaling

Cited by 51 publications

References 30 publications

H Long Terminal Repeat-Associating 2 (HHLA2) is a Biomarker of Advanced Stage Hepatocellular Carcinoma and Promotes Tumor Cell Development In Vitro

H Long Terminal Repeat-Associating 2 (HHLA2) is a Biomarker of Advanced Stage Hepatocellular Carcinoma and Promotes Tumor Cell Development In Vitro

B7-H7 Is Inducible on T Cells to Regulate Their Immune Response and Serves as a Marker for Exhaustion

Recent Advancements in the Mechanisms Underlying Resistance to PD-1/PD-L1 Blockade Immunotherapy

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