KIR3DL3 Is an Inhibitory Receptor for HHLA2 that Mediates an Alternative Immunoinhibitory Pathway to PD1

Bhatt, Rupal S.; Berjis, Abdulla; Konge, Julie C.; Mahoney, Kathleen M.; Klee, Alyssa N.; Freeman, Samuel S.; Chen, Chun-Hau; Jegede, Opeyemi; Catalano, Paul J.; Pignon, Jean‐Christophe; Sticco-Ivins, Maura; Zhu, Baogong; Hua, Peng; Soden, Jo; Zhu, Jie; McDermott, David F.; Arulanandam, Antonio R.; Signoretti, Sabina; Freeman, Gordon J.

doi:10.1158/2326-6066.cir-20-0315

Cited by 74 publications

(86 citation statements)

References 48 publications

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“… 12 Moreover, Rieder et al discovered that HHLA2 was insufficient to evaluate the proliferation and cytokine production of T cells stimulated with OKT3 (the anti-CD3 monoclonal antibody), which may result from the differential effects of various α-CD3 clones on T cell function. 13 Recent studies demonstrated inhibitory effects of HHLA2 on T cells and NK cells, when interacts with the inhibitory receptor KIRR3DL3, 14 suggesting HHLA2 as a potential immunotherapeutic target for cancer. In this study, we focused on the in situ distribution of HHLA2 in HCC tissue, and identified a high expression of HHLA2 on activated monocytes/macrophages in the peri-tumor region of HCC.…”

Section: Discussionmentioning

confidence: 99%

HHLA2 Expression is Associated with Poor Survival in Patients with Hepatocellular Carcinoma

Xu¹,

Huang²,

Yu³

et al. 2021

BTT

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Background Human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) is a member of the B7 family; however, little is known regarding its expression and clinical relevance in hepatocellular carcinoma (HCC). Methods To better characterize HHLA2 expression in HCC, we analyzed its expression by in situ staining and further investigated its correlation with immune infiltration and patient prognosis. Results HHLA2 was primarily expressed in the peri-tumor region of HCC tissues and co-localized with CD68 + monocytes/macrophages. In vitro analysis and multi-immunofluorescence staining showed up-regulated HHLA2 expression in tumor-activated monocytes/macrophages, and HHLA2 + monocytes/macrophages expressed high levels of HLA-DR in HCC tissue. A correlation analysis showed that samples displaying high HHLA2 expression in the peri-tumor region had significant tumor infiltration of CD204 + and CD11b + cells, and low expression of genes associated with an anti-tumor immune response. The high level of peri-tumoral HHLA2 expression was associated with a poor patient overall survival (OS; P = 0.008). A multivariate analysis revealed that HHLA2 expression in the peri-tumor region was an independent prognostic factor for OS (hazard ratio = 1.872, p = 0.003). Moreover, the expression of HHLA2 was negatively correlated with PD-L1, and patients exhibiting HHLA2 and programmed cell death-ligand 1(PD-L1) co-expression had the shortest survival time. Conclusion HHLA2 expression represented an immunosuppressive microenvironment in HCC, and may serve as a potential target for immunotherapy.

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Section: Discussionmentioning

confidence: 99%

HHLA2 Expression is Associated with Poor Survival in Patients with Hepatocellular Carcinoma

Xu¹,

Huang²,

Yu³

et al. 2021

BTT

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“…Several studies have shown that ligation of B7-H7 can either stimulate or inhibit T cell responses (2,4). 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).…”

Section: Discussionmentioning

confidence: 99%

“…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). It is therefore plausible that other inhibitory receptors that mediate immune regulation by B7-H7 exist.…”

Section: Discussionmentioning

confidence: 99%

“…Since different groups presented conflicting data on the function of B7-H7, a concept of dual functionality was proposed, as is the case of CD80/CD86 and CD28/CTLA-4. Along these lines, Bhatt et al recently proposed that CD28H acts as an immunostimulatory receptor whereas KIR3DL3 instead inhibit immune responses upon ligation of B7-H7 (14).…”

Section: Introductionmentioning

confidence: 99%

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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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“…If the cells are expressing the receptor for the target-of-interest, this can be detected by increased target binding to the surface of the cell. This approach has been successfully utilized to deorphanize secreted factors [53], interactions between immune receptors [54], or identify glycan-dependent recognition of specific ligands [55]. However, the generation and management of cDNA libraries that have significant coverage of membrane proteins can be expensive and not accessible to many investigators.…”

Section: Cell-based Library Formatsmentioning

confidence: 99%

Unbiased Identification of Extracellular Protein–Protein Interactions for Drug Target and Biologic Drug Discovery

Cao¹,

Martínez‐Martín²

2022

High-Throughput Screening for Drug Discovery

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Technological improvements in unbiased screening have accelerated drug target discovery. In particular, membrane-embedded and secreted proteins have gained attention because of their ability to orchestrate intercellular communication. Dysregulation of their extracellular protein–protein interactions (ePPIs) underlies the initiation and progression of many human diseases. Practically, ePPIs are also accessible for modulation by therapeutics since they operate outside of the plasma membrane. Therefore, it is unsurprising that while these proteins make up about 30% of human genes, they encompass the majority of drug targets approved by the FDA. Even so, most secreted and membrane proteins remain uncharacterized in terms of binding partners and cellular functions. To address this, a number of approaches have been developed to overcome challenges associated with membrane protein biology and ePPI discovery. This chapter will cover recent advances that use high-throughput methods to move towards the generation of a comprehensive network of ePPIs in humans for future targeted drug discovery.

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KIR3DL3 Is an Inhibitory Receptor for HHLA2 that Mediates an Alternative Immunoinhibitory Pathway to PD1

Cited by 74 publications

References 48 publications

HHLA2 Expression is Associated with Poor Survival in Patients with Hepatocellular Carcinoma

HHLA2 Expression is Associated with Poor Survival in Patients with Hepatocellular Carcinoma

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

Unbiased Identification of Extracellular Protein–Protein Interactions for Drug Target and Biologic Drug Discovery

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