RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance

Xiao, Yanping; Yu, Sanhong; Zhu, Baogong; Bedoret, Denis; Bu, Xia; Francisco, Loise; Hua, Peng; Duke‐Cohan, Jonathan S.; Umetsu, Dale T.; Sharpe, Arlene H.; DeKruyff, Rosemarie H.; Freeman, Gordon J.

doi:10.1084/jem.20130790

Cited by 263 publications

(245 citation statements)

References 53 publications

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“…Thus far, clinical studies with the PD-L1 and PD-1 blockade have not rigorously examined or specifically quantified PD-L1 expression on APC subsets versus tumor cells in TDLNs and tumor tissues in cancer patients (2). Our data suggest that PD-L1 and PD-1 blockade not only targets the T cell effector phase in the tumor microenvironment, but also (17,18). Despite this, Abs against PD-1 and PD-L1 appear to have comparable clinical efficacy and toxicity (2).…”

Section: Discussionmentioning

confidence: 88%

Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade–mediated tumor regression

Lin

Wei

Hurt³

et al. 2018

Journal of Clinical Investigation

473

373

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Section: Discussionmentioning

confidence: 88%

Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade–mediated tumor regression

Lin

Wei

Hurt³

et al. 2018

Journal of Clinical Investigation

473

373

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“…This finding came as a surprise because CD80 had been previously identified as a functional ligand for CD28 and cytotoxic T lymphocyte antigen-4 (CTLA-4) (14,15). PD-L2 was also found to interact with repulsive guidance molecule family member b (RGMb), a molecule that is highly enriched in lung macrophages and may be required for induction of respiratory tolerance (16). With at least five interacting molecules in the PD-1/PD-L1 pathway (referred to as the PD pathway) (Figure 1), further studies will be required to understand the relative contributions of these molecules during activation or suppression of T cells.…”

Section: The Pd Pathwaymentioning

confidence: 99%

Anti–PD-1/PD-L1 therapy of human cancer: past, present, and future

Chen

Han

2015

Journal of Clinical Investigation

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970

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“…7 More interestingly, PDL1 and PDL2 may bind to another co-stimulatory molecule, transducing stimulatory signals to T-cells in a mechanism analogous to the CTLA4/CD28 axis. 8 …”

Section: Pdl1 Is Expressed Constitutively On T-cells B-cells Dendrimentioning

confidence: 99%

Pembrolizumab (Keytruda)

Kwok

Yau

Chiu

et al. 2016

Human Vaccines & Immunotherapeutics

301

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The programmed cell death protein 1 (PD1) is one of the checkpoints that regulates the immune response. Ligation of PD1 with its ligands PDL1 and PDL2 results in transduction of negative signals to T-cells. PD1 expression is an important mechanism contributing to the exhausted effector T-cell phenotype. The expression of PD1 on effector T-cells and PDL1 on neoplastic cells enables tumor cells to evade anti-tumor immunity. Blockade of PD1 is an important immunotherapeutic strategy for cancers. Pembrolizumab (Keytruda) is a humanized monoclonal anti-PD1 antibody that has been extensively investigated in numerous malignancies. In melanoma refractory to targeted therapy, pembrolizumab induced overall response rates (ORRs) of 21-34%. It was superior to another immune checkpoint inhibitor ipilimumab (Yervoy) in stage III/IV unresectable melanoma. In refractory non-small cell lung cancer (NSCLC), pembrolizumab induced ORRs of 19-25%. Based on these results, pembrolizumab was approved by the USA FDA for the treatment of advanced melanoma and NSCLC. Tumor cell PDL1 expression may be a valid response predictor. Molecular analysis also showed that tumors with high gene mutation burdens, which might result in the formation of more tumor-related neo-antigens, had better responses to pembrolizumab. In malignancies including lymphomas and other solid tumors, preliminary data showed that ORRs of around 20-50 % could be achieved. Adverse events occurred in up to 60% of patients, but grade 3/4 toxicities were observed in <10% of cases. Immune-related adverse events including thyroid dysfunction, hepatitis and pneumonitis are more serious and may lead to cessation of treatment.

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RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance

Abstract: Interaction between the inhibitory molecule PD-L2 on dendritic cells and repulsive guidance molecule b (RGMb) on lung macrophages is required to establish respiratory tolerance.

Cited by 263 publications

References 53 publications

Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade–mediated tumor regression

Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade–mediated tumor regression

Anti–PD-1/PD-L1 therapy of human cancer: past, present, and future

Pembrolizumab (Keytruda)

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