The effect of combining PD-1 agonist and low-dose Interleukin-2 on treating systemic lupus erythematosus

Wang, Bing; Chen, Can; Liu, Xia; Zhou, Shuang; Xu, Ting; Wu, Min

doi:10.3389/fimmu.2023.1111005

Cited by 7 publications

(3 citation statements)

References 103 publications

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“…There are a few reasons why PD-1 agonists might increase cancer risk. Activation of the PD-1 pathway can inactivate tumor-infiltrating lymphocytes, thus evading immune surveillance [ 25 ]. Moreover, PD-1 agonists could increase the expression of PD-L1 on cancer cells, making these cells more resistant to T cell-mediated killing.…”

Section: Discussionmentioning

confidence: 99%

PD-1 signaling uncovers a pathogenic subset of T cells in inflammatory arthritis

Straube,

Bukhari,

Lerrer

et al. 2024

Arthritis Res Ther

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Background PD-1 is an immune checkpoint on T cells, and interventions to block this receptor result in T cell activation and enhanced immune response to tumors and pathogens. Reciprocally, despite a decade of research, approaches to treat autoimmunity with PD-1 agonists have only had limited successful. To resolve this, new methods must be developed to augment PD-1 function beyond engaging the receptor. Methods We conducted a flow cytometry analysis of T cells isolated from the peripheral blood and synovial fluid of patients with rheumatoid arthritis. In addition, we performed a genome-wide CRISPR/Cas9 screen to identify genes associated with PD-1 signaling. We further analyzed genes involved in PD-1 signaling using publicly available bulk and single-cell RNA sequencing datasets. Results Our screen confirmed known regulators in proximal PD-1 signaling and, importantly, identified an additional 1112 unique genes related to PD-1 ability to inhibit T cell functions. These genes were strongly associated with the response of cancer patients to PD-1 blockades and with high tumor immune dysfunction and exclusion scores, confirming their role downstream of PD-1. Functional annotation revealed that the most significant genes uncovered were those associated with known immune regulation processes. Remarkably, these genes were considerably downregulated in T cells isolated from patients with inflammatory arthritis, supporting their overall inhibitory functions. A study of rheumatoid arthritis single-cell RNA sequencing data demonstrated that five genes, KLRG1, CRTAM, SLAMF7, PTPN2, and KLRD1, were downregulated in activated and effector T cells isolated from synovial fluids. Backgating these genes to canonical cytotoxic T cell signatures revealed PD-1+ HLA-DRHIGH KLRG1LOW T cells as a novel inflammatory subset of T cells. Conclusions We concluded that PD-1+ HLA-DRHIGH KLRG1LOW T cells are a potential target for future PD-1 agonists to treat inflammatory diseases. Our study uncovers new genes associated with PD-1 downstream functions and, therefore, provides a comprehensive resource for additional studies that are much needed to characterize the role of PD-1 in the synovial subset of T cells.

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Section: Discussionmentioning

confidence: 99%

PD-1 signaling uncovers a pathogenic subset of T cells in inflammatory arthritis

Straube,

Bukhari,

Lerrer

et al. 2024

Arthritis Res Ther

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“…In addition, blocking [44] or activating [45] PD-1 can improve the survival of lupus mice. In addition, the combination of PD-1 agonist and low-dose IL-2 may have better therapeutic efficacy in SLE [46]. The susceptibility to SLE is also related to PD1.3/PD1.5 polymorphism, while the PD1.6 polymorphism is possibly protective for SLE [47].…”

Section: Discussionmentioning

confidence: 99%

The effect of PD-1/PD-L1 signaling axis on the interaction between CD19+B cells and CD4+T cells in peripheral blood of patients with systemic lupus erythematosus

Xie,

Dai,

et al. 2023

Adv Rheumatol

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Background The defect of B cell self-tolerance and the continuous antigen presentation by T cells (TCs) mediated by autoreactive B cells (BCs) play a key role in the occurrence and development of systemic lupus erythematosus (SLE). PD-1/PD-L1 signaling axis negatively regulates the immune response of TCs after activation and maintains immune tolerance. However, the effect of PD-1/PD-L1 signaling axis on the interaction between CD19+B/CD4+TCs in the peripheral blood of patients with SLE has not been studied in detail. Methods PD-1/PD-L1 and Ki-67 levels in peripheral blood (PB) of 50 SLE patients and 41 healthy controls (HCs) were detected through flow cytometry, and then the expression of PD-1+/−cells and PD-L1+/−cells Ki-67 was further analyzed. CD19+B/CD4+TCs were separated for cell culture and the supernatant was collected to determine proliferation and differentiation of TCs. IL-10 and IFN-γ secretion in the supernatant was also determined using ELISA. Results The PD-1, PD-L1, and Ki-67 levels on CD19+B/CD4+TCs in patients with SLE were higher than HCs. In CD19+B/CD4+TCs of SLE patients, the proliferative activity of PD-L1+ cells was higher than that of PD-L1− cells, and the proliferative activity of PD-1+ cells was higher than that of PD-1− cells. In the system co-culturing CD19+B/CD4+TCs from HCs/SLE patients, activated BCs promoted TCs proliferation and PD-L1 expression among TCs. Addition of anti-PD-L1 to co-culture system restored the proliferation of TCs, and inhibited IL-10/IFN-γ level. The addition of anti-PD-L1 to co-culture system also restored Tfh and downregulated Treg in HCs. Conclusions Axis of PD-1/PD-L1 on CD19+B/CD4+TCs in PB of SLE patients is abnormal, and cell proliferation is abnormal. In CD19+B/CD4+TCs of SLE patients, the proliferative activity of PD-L1+ and PD-1+ cells compared with PD-L1− and PD-1− cells in SLE patients, respectively. CD19+B/CD4+TCs in SLE patients can interact through PD-1/PD-L1.

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“…Although the potential of activating the PD-1 co-inhibitory pathway to alleviate autoimmunity is still being explored, it appears to be a promising therapeutic approach. In fact, there are PD-1 agonists ongoing in phase I and II in clinical trials, and researchers are collecting information to propose novel strategies such as combining low doses of IL-2 with PD-1 agonists [172]. Certainly, this has the potential to revolutionize conventional strategies and bring us closer to the era of precision medicine.…”

Section: Pd-1 Agonistsmentioning

confidence: 99%

Exploring the Role of PD-1 in the Autoimmune Response: Insights into Its Implication in Systemic Lupus Erythematosus

Sagrero-Fabela,

Chávez-Mireles,

Salazar-Camarena

et al. 2024

Preprint

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Despite advances in our knowledge of systemic lupus erythematosus (SLE) has increased over time, there are still many challenges in deciphering the precise mechanisms involved in the development and progression of the disease. Recent evidence has raised questions about the effectiveness of the programmed cell death protein 1 (PD-1) in suppressing autoreactive CD4+ T cells during the autoimmune response. Research has ventured into investigate the potential impact of PD-1 on various CD4+ T cell subpopulations, including T follicular helper (Tfh) cells, circulating Tfh (cTfh) cells, and T peripheral helper (Tph) cells, all of which exhibit substantial PD-1 expression and have been closely related with several autoimmune disorders including SLE. This review aims to highlight the complex role of PD-1 in autoimmunity and emphasizes the imperative for further research to elucidate its functions during autoreactive T-cell response. Additionally, we address the potential of PD-1 or its ligands as a possible therapeutic target in SLE.

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The effect of combining PD-1 agonist and low-dose Interleukin-2 on treating systemic lupus erythematosus

Cited by 7 publications

References 103 publications

PD-1 signaling uncovers a pathogenic subset of T cells in inflammatory arthritis

PD-1 signaling uncovers a pathogenic subset of T cells in inflammatory arthritis

The effect of PD-1/PD-L1 signaling axis on the interaction between CD19+B cells and CD4+T cells in peripheral blood of patients with systemic lupus erythematosus

Exploring the Role of PD-1 in the Autoimmune Response: Insights into Its Implication in Systemic Lupus Erythematosus

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