CD84 regulates PD-1/PD-L1 expression and function in chronic lymphocytic leukemia

Lewinsky, Hadas; Barak, Avital; Huber, Victoria; Kramer, Matthias P.; Radomir, Lihi; Sever, Lital; Orr, Irit; Mirkin, Vita; Dezorella, Nili; Shapiro, Mika; Cohen, Yosef; Shvidel, Lev; Seiffert, Martina; Herishanu, Yair; Becker-Herman, Shirly; Shachar, Idit

doi:10.1172/jci96610

Cited by 51 publications

(45 citation statements)

References 48 publications

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“…Ingenuity Pathway Analysis (IPA) and Metascape analysis resulted in enrichment of T-lymphocyte-related processes (Metascape: "Reguation of T cell activation," "Reguation of T cell receptor signaling pathway," "T cell costimulation," "T cell differentiation," IPA: "Cell Proliferation of T Lymphocytes," "T cell homeostasis," "Proliferation of lymphocytes" (Additional file 1: Figure S8a). These findings are in line with recent reports demonstrating that CD8 + T cells from patients with chronic lymphocytic leukemia exhibit features of T cell exhaustion, i.e., lower proliferative and cytotoxic capacity and increased expression of inhibitory receptors (e.g., CTLA-4, TIGIT, Lag3, PD-1), suggesting both CLL and T cell-specific changes leading to decreased ability to eliminate malignant cells [55][56][57][58].…”

Section: Identification Of Epigenetically Deregulated Transcripts In Cllsupporting

confidence: 92%

“…It was also reported as a selective marker of neoplastic B cells and HSCs from CLL patients [66]. LILRB4 targeting, either by antibodies or by CAR-T cells, impeded AML development [56,57]. CD276 overexpression, on the other hand, was linked to anti-apoptosis in colorectal cancer through activation of Jak2-STAT3 signaling pathway, and as a result, increased expression of antiapoptotic protein Bcl-2 [67].…”

Section: Discussionmentioning

confidence: 99%

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Methylome-based cell-of-origin modeling (Methyl-COOM) identifies aberrant expression of immune regulatory molecules in CLL

et al. 2020

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Section: Identification Of Epigenetically Deregulated Transcripts In Cllsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Methylome-based cell-of-origin modeling (Methyl-COOM) identifies aberrant expression of immune regulatory molecules in CLL

et al. 2020

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“…24 The T cells split into 6 clusters, namely, main T cells, inflammatory T cells, CD40LG 1 cells, CD84 1 cells, CCR6 1 cells, and natural killer T cells ( Inflammatory T cells were distinguished by high expression of the AD-related cytokine CSF2, 25 but also by abundantly expressed type 2 cytokine IL13, type 22 cytokine IL22, TNFRSF4/OX40, and TNFSF14/LIGHT, likely representing activated and polarized T cells. The CD40LG 1 , CD84 1 , and CCR6 1 subgroups likely represent T cells with specialized roles in mediating B-cell activation/class switching, immune regulation via formation of hemophilic dimers, 26 and recruitment of T H 17 and regulatory T cells, respectively. Finally, natural killer T cells not only expressed CD3D but also expressed NKG7, GZMA, and GZMK, highlighting their cytotoxic nature.…”

Section: Strategy For Scrna-seq and Data Analysismentioning

confidence: 99%

Single-cell transcriptome analysis of human skin identifies novel fibroblast subpopulation and enrichment of immune subsets in atopic dermatitis

Suryawanshi

Morozov

et al. 2020

Journal of Allergy and Clinical Immunology

312

351

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Background: Atopic dermatitis (AD) is a prevalent inflammatory skin disease with a complex pathogenesis involving immune cell and epidermal abnormalities. Despite whole tissue biopsy studies that have advanced the mechanistic understanding of AD, single cell-based molecular alterations are largely unknown. Objective: Our aims were to construct a detailed, high-resolution atlas of cell populations and assess variability in cell composition and cell-specific gene expression in the skin of patients with AD versus in controls. Methods: We performed single-cell RNA sequencing on skin biopsy specimens from 5 patients with AD (4 lesional samples and 5 nonlesional samples) and 7 healthy control subjects, using 103 Genomics. Results: We created transcriptomic profiles for 39,042 AD (lesional and nonlesional) and healthy skin cells. Fibroblasts demonstrated a novel COL6A5 1 COL18A1 1 subpopulation that was unique to lesional AD and expressed CCL2 and CCL19 cytokines. A corresponding LAMP3 1 dendritic cell (DC) population that expressed the CCL19 receptor CCR7 was also unique to AD lesions, illustrating a potential role for fibroblast signaling to immune cells. The lesional AD samples were characterized by expansion of inflammatory DCs (CD1A 1 FCER1A 1) and tissue-resident memory T cells (CD69 1 CD103 1). The frequencies of type 2 (IL13 1)/type 22 (IL22 1) T cells were higher than those of type 1 (IFNG 1) in lesional AD, whereas this ratio was slightly diminished in nonlesional AD and further diminished in controls. Conclusion: AD lesions were characterized by expanded type 2/type 22 T cells and inflammatory DCs, and by a unique inflammatory fibroblast that may interact with immune cells to regulate lymphoid cell organization and type 2 inflammation.

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“…The proposed mechanism of action involves the PI3K/AKT signaling cascade and the activation of the transcription factor STAT3. In addition, the authors showed that CD84 silencing not only downregulates PD-L1 expression on CLL cells and in the microenvironment, but it also affects PD-1 expression on the T cell compartment, suggesting a central role of CD84 in driving immunomodulatory signaling [63]. Lastly, treatment with Bruton's tyrosine kinase (BTK) inhibitor ibrutinib was also found to decrease PD-1/PD-L1 expression, thereby affecting T cell proliferation and pseudoexhaustion, with important implication in the disease outcome [64][65][66][67][68][69].…”

Section: Programmed Cell Death 1 (Pd-1)/programmed Cell Death Ligandmentioning

confidence: 99%

Immune Response Dysfunction in Chronic Lymphocytic Leukemia: Dissecting Molecular Mechanisms and Microenvironmental Conditions

Arruga

Gyau

Iannello

et al. 2020

IJMS

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Representing the major cause of morbidity and mortality for chronic lymphocytic leukemia (CLL) patients, immunosuppression is a common feature of the disease. Effectors of the innate and the adaptive immune response show marked dysfunction and skewing towards the generation of a tolerant environment that favors disease expansion. Major deregulations are found in the T lymphocyte compartment, with inhibition of CD8+ cytotoxic and CD4+ activated effector T cells, replaced by exhausted and more tolerogenic subsets. Likewise, differentiation of monocytes towards a suppressive M2-like phenotype is induced at the expense of pro-inflammatory sub-populations. Thanks to their B-regulatory phenotype, leukemic cells play a central role in driving immunosuppression, progressively inhibiting immune responses. A number of signaling cascades triggered by soluble mediators and cell–cell contacts contribute to immunomodulation in CLL, fostered also by local environmental conditions, such as hypoxia and derived metabolic acidosis. Specifically, molecular pathways modulating T-cell activity in CLL, spanning from the best known cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death 1 (PD-1) to the emerging T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT)/CD155 axes, are attracting increasing research interest and therapeutic relevance also in the CLL field. On the other hand, in the microenvironment, the B cell receptor (BCR), which is undoubtedly the master regulator of leukemic cell behavior, plays an important role in orchestrating immune responses, as well. Lastly, local conditions of hypoxia, typical of the lymphoid niche, have major effects both on CLL cells and on non-leukemic immune cells, partly mediated through adenosine signaling, for which novel specific inhibitors are currently under development. In summary, this review will provide an overview of the molecular and microenvironmental mechanisms that modify innate and adaptive immune responses of CLL patients, focusing attention on those that may have therapeutic implications.

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CD84 regulates PD-1/PD-L1 expression and function in chronic lymphocytic leukemia

Cited by 51 publications

References 48 publications

Methylome-based cell-of-origin modeling (Methyl-COOM) identifies aberrant expression of immune regulatory molecules in CLL

Methylome-based cell-of-origin modeling (Methyl-COOM) identifies aberrant expression of immune regulatory molecules in CLL

Single-cell transcriptome analysis of human skin identifies novel fibroblast subpopulation and enrichment of immune subsets in atopic dermatitis

Immune Response Dysfunction in Chronic Lymphocytic Leukemia: Dissecting Molecular Mechanisms and Microenvironmental Conditions

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