Disrupting CD38-driven T cell dysfunction restores sensitivity to cancer immunotherapy DOI Creative Commons
Or‐Yam Revach, Angelina M. Cicerchia, Ofir Shorer

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 14, 2024

A central problem in cancer immunotherapy with immune checkpoint blockade (ICB) is the development of resistance, which affects 50% patients metastatic melanoma 1,2 . T cell exhaustion, resulting from chronic antigen exposure tumour microenvironment, a major driver ICB resistance 3 Here, we show that CD38, an ecto-enzyme involved nicotinamide adenine dinucleotide (NAD + ) catabolism, highly expressed exhausted CD8 cells and associated resistance. Tumour-derived CD38 hi are dysfunctional, characterised by impaired proliferative capacity, effector function, dysregulated mitochondrial bioenergetics. Genetic pharmacological murine patient-derived organotypic models (MDOTS/PDOTS) enhanced immunity overcame Mechanistically, disrupting activity restored cellular NAD pools, improved increased proliferation, augmented sensitivity. Taken together, these data demonstrate role for CD38-NAD axis promoting exhaustion establish efficacy directed therapeutic strategies to overcome using clinically relevant, 3D models.

Language: Английский

Abnormalities of T cells in systemic lupus erythematosus: new insights in pathogenesis and therapeutic strategies DOI Creative Commons
Hao Li,

Afroditi Boulougoura,

Yushiro Endo

et al.

Journal of Autoimmunity, Journal Year: 2022, Volume and Issue: 132, P. 102870 - 102870

Published: July 22, 2022

Language: Английский

Citations

115
Systemic Lupus Erythematosus Pathogenesis: Interferon and Beyond DOI Creative Commons
Simone Caielli,

Zurong Wan,

Virginia Pascual

et al.

Annual Review of Immunology, Journal Year: 2023, Volume and Issue: 41(1), P. 533 - 560

Published: Feb. 28, 2023

Autoreactive B cells and interferons are central players in systemic lupus erythematosus (SLE) pathogenesis. The partial success of drugs targeting these pathways, however, supports heterogeneity upstream mechanisms contributing to disease In this review, we focus on recent insights from genetic immune monitoring studies patients that refining our understanding basic mechanisms. Among them, novel mutations genes affecting intrinsic cell activation or clearance interferogenic nucleic acids have been described. Mitochondria emerged as relevant inducers and/or amplifiers SLE pathogenesis through a variety include disruption organelle integrity compartmentalization, defective metabolism, failure quality control measures. These result extra- intracellular release well innate adaptive activation. A classic autoantibody specificities found recapitulate alterations associated with monogenic trigger amplification loops. Finally, atypical extrafollicular T helper subsets proposed contribute the generation autoantibodies. Overall, provide opportunities deepen immunophenotypic surveillance open door patient stratification personalized, rational approaches therapy.

Language: Английский

Citations

109
Systemic lupus erythematosus: one year in review 2023 DOI Open Access
Dina Zucchi, Ettore Silvagni, Elena Elefante

et al.

Clinical and Experimental Rheumatology, Journal Year: 2023, Volume and Issue: unknown

Published: May 3, 2023

Language: Английский

Citations

47
The immunology of systemic lupus erythematosus DOI
George C. Tsokos

Nature Immunology, Journal Year: 2024, Volume and Issue: 25(8), P. 1332 - 1343

Published: July 15, 2024

Language: Английский

Citations

28
Inhibition of CD38 enzymatic activity enhances CAR-T cell immune-therapeutic efficacy by repressing glycolytic metabolism DOI Creative Commons
Yue Huang,

Mi Shao,

Xinyi Teng

et al.

Cell Reports Medicine, Journal Year: 2024, Volume and Issue: 5(2), P. 101400 - 101400

Published: Feb. 1, 2024

Chimeric antigen receptor (CAR)-T therapy has shown superior efficacy against hematopoietic malignancies. However, many patients failed to achieve sustainable tumor control partially due CAR-T cell exhaustion and limited persistence. In this study, by performing single-cell multi-omics data analysis on patient-derived cells, we identify CD38 as a potential hallmark of exhausted which is positively correlated with exhaustion-related transcription factors further confirmed in vitro models. Moreover, inhibiting activity reverses tonic signaling- or antigen-induced independent single-chain variable fragment design costimulatory domain, resulting improved cytotoxicity antitumor response. Mechanistically, inhibition synergizes the downregulation CD38-cADPR -Ca2+ signaling activation CD38-NAD+-SIRT1 axis suppress glycolysis. Collectively, our findings shed light role suggest clinical applications enhancing persistence therapy.

Language: Английский

Citations

19
Single cell dynamics of tumor specificity vs bystander activity in CD8+ T cells define the diverse immune landscapes in colorectal cancer DOI Creative Commons
Daniel Borràs, Sara Verbandt,

Markus Außerhofer

et al.

Cell Discovery, Journal Year: 2023, Volume and Issue: 9(1)

Published: Nov. 15, 2023

Abstract CD8 + T cell activation via immune checkpoint blockade (ICB) is successful in microsatellite instable (MSI) colorectal cancer (CRC) patients. By comparison, the success of immunotherapy against stable (MSS) CRC limited. Little known about most critical features cells that together determine diverse landscapes and contrasting ICB responses. Hence, we pursued a deep single mapping on transcriptomic receptor (TCR) repertoire levels patient cohort, with additional surface proteome validation. This revealed dynamics are underscored by complex interactions between interferon-γ signaling, tumor reactivity, TCR repertoire, (predicted) antigen-specificities, environmental cues like gut microbiome or colon tissue-specific ‘self-like’ features. MSI showed tumor-specific reminiscent canonical ‘T hot’ tumors, whereas MSS exhibited unspecific bystander-like was accompanied inflammation ‘pseudo-T tumors. Consequently, overlapping phenotypic differed dramatically their antigen-specificities. Given high discriminating potential for features/specificities, used tumor-reactive signaling modules to build bulk transcriptome classification “Immune Subtype Classification” (ISC) successfully distinguished various tumoral prognostic value predicted responses Thus, deliver unique map drives novel landscape classification, relevance decision-making.

Language: Английский

Citations

38
NAD+ exhaustion by CD38 upregulation contributes to blood pressure elevation and vascular damage in hypertension DOI Creative Commons
Yumin Qiu,

Shiyue Xu,

Xi Chen

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Sept. 18, 2023

Hypertension is characterized by endothelial dysfunction and arterial stiffness, which contribute to the pathogenesis of atherosclerotic cardiovascular diseases. Nicotinamide adenine dinucleotide (NAD+) an indispensable cofactor in all living cells that involved fundamental biological processes. However, hypertensive patients, alterations NAD+ levels their relation with blood pressure (BP) elevation vascular damage have not yet been studied. Here we reported patients exhibited lower levels, as detected high-performance liquid chromatography-mass spectrometry (HPLC-MS), both peripheral mononuclear (PBMCs) aortas, was parallel dysfunction. boosting therapy nicotinamide mononucleotide (NMN) supplement reduced BP ameliorated (NCT04903210) AngII-induced mice. Upregulation CD38 led exhaustion reducing NMN bioavailability. Pro-inflammatory macrophages infiltration increase IL-1β generation derived from pro-inflammatory resulted higher expression activating JAK1-STAT1 signaling pathway. KO, inhibitors treatment, or adeno-associated virus (AAV)-mediated knockdown lowered improved The present study demonstrated for first time activation subsequently accelerated degradation due enhanced macrophage-derived production responsible hypertension. can be used a novel therapeutic strategy management patients.

Language: Английский

Citations

26
Metabolic dysregulation of lymphocytes in autoimmune diseases DOI
Shuyi Wang, Niansheng Yang, Hui Zhang

et al.

Trends in Endocrinology and Metabolism, Journal Year: 2024, Volume and Issue: 35(7), P. 624 - 637

Published: Feb. 13, 2024

Language: Английский

Citations

13
Mitochondrial Dysfunction in Systemic Lupus Erythematosus with a Focus on Lupus Nephritis DOI Open Access
Matthieu Halfon, Aurel T. Tankeu, Camillo Ribi

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(11), P. 6162 - 6162

Published: June 3, 2024

Systemic lupus erythematosus (SLE) is an autoimmune disease affecting mostly women of child-bearing age. Immune dysfunction in SLE results from disrupted apoptosis which lead to unregulated interferon (IFN) stimulation and the production autoantibodies, leading immune complex formation, complement activation, organ damage. Lupus nephritis (LN) a common severe complication SLE, impacting approximately 30% 40% patients. Recent studies have demonstrated alteration mitochondrial homeostasis Mitochondrial contributes significantly pathogenesis by enhancing type 1 IFN through various pathways involving neutrophils, platelets, T cells. Defective mitophagy, process clearing damaged mitochondria, exacerbates this cycle, increased dysregulation. In review, we aim detail physiopathological link between activity SLE. Additionally, will explore potential role mitochondria as biomarkers therapeutic targets with specific focus on LN. LN, abnormalities are observed renal cells, correlating progression fibrosis. Studies exploring cell-free DNA biomarker LN shown promising but preliminary results, necessitating further validation standardization. Therapeutically targeting using drugs like metformin or mTOR inhibitors, shows modulating responses improving clinical outcomes. The interplay dysregulation, involvement underscores need for comprehensive research innovative strategies. Understanding dynamics their impact offers avenues developing personalized treatments non-invasive biomarkers, ultimately outcomes

Language: Английский

Citations

11
Novel mitophagy inducer alleviates lupus nephritis by reducing myeloid cell activation and autoantigen presentation DOI Creative Commons
Huijing Wang,

Mingdi Shen,

Yanhong Ma

et al.

Kidney International, Journal Year: 2024, Volume and Issue: 105(4), P. 759 - 774

Published: Jan. 29, 2024

Lupus nephritis (LN) is one of the most severe manifestations systemic lupus erythematosus (SLE), but its mechanism onset remains unclear. Since impaired mitophagy has been implicated in multiple organs SLE, we hypothesized that dysfunction critical development LN and pharmacologically targeting would ameliorate this disease. Therefore, lupus-prone MRL/MpJ-Faslpr (MRL/lpr) NZBWF1/J mice were treated with a novel inducer, UMI-77, during their LN. This treatment effectively mitigated kidney inflammation damage as assessed by histology flow cytometry. Furthermore, dendritic cell (DC)-T coculture assay indicated UMI-77 attenuated DC function drive T proliferation did not directly influence potent mice. also restored mitochondrial proinflammatory phenotypes DCs. Adoptive transfer DCs from MRL/lpr augmented serum anti-dsDNA IgG, urine protein infiltration MRL/MpJ mice, which could be prevented either treating donors vivo or UMI-77. myeloid cells patients vitro evidenced increased ATP levels. Thus, enhancing SLE restrains autoimmunity limits for development. Hence, our findings suggest tangible pathway to treat

Language: Английский

Citations

10