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

Cell-Intrinsic CD38 Expression Sustains Exhausted CD8 + T Cells by Regulating Their Survival and Metabolism during Chronic Viral Infection DOI
Julia M. DeRogatis, Emily N. Neubert,

Karla M. Viramontes

et al.

Journal of Virology, Journal Year: 2023, Volume and Issue: 97(4)

Published: April 11, 2023

Our study shows how CD38 expression is regulated on CD8 + T cells responding during acute and chronic viral infection. We observed higher levels infection compared to

Language: Английский

Citations

15
Integrated analyses revealed the potential role and immune link of mitochondrial dysfunction between periodontitis and type 2 diabetes mellitus DOI

Shengyuan Pan,

Lanxin Yang, Wenjie Zhong

et al.

International Immunopharmacology, Journal Year: 2024, Volume and Issue: 130, P. 111796 - 111796

Published: March 1, 2024

Language: Английский

Citations

5
Pathological mechanisms and crosstalk among different forms of cell death in systemic lupus erythematosus DOI
Yue Xu, Pengchong Li, Ketian Li

et al.

Journal of Autoimmunity, Journal Year: 2022, Volume and Issue: 132, P. 102890 - 102890

Published: Aug. 10, 2022

Language: Английский

Citations

20
Mitochondrial bioenergetic changes in systemic lupus erythematosus immune cell subsets: Contributions to pathogenesis and clinical applications DOI Creative Commons
Anjali Yennemadi, Joseph Keane, Gina Leisching

et al.

Lupus, Journal Year: 2023, Volume and Issue: 32(5), P. 603 - 611

Published: March 13, 2023

The association of dysregulated metabolism in systemic lupus erythematosus (SLE) pathogenesis has prompted investigations into metabolic rewiring and the involvement mitochondrial as a driver disease through NLRP3 inflammasome activation, disruption DNA maintenance, pro-inflammatory cytokine release. use Agilent Seahorse Technology to gain functional situ insights selected cell types from SLE patients identified key parameters that are during disease. Mitochondrial assessments specifically can detect dysfunction oxygen consumption rate (OCR), spare respiratory capacity, maximal respiration measurements, which, when coupled with activity scores could show potential markers activity. CD4+ CD8 + T cells have been assessed this way rate, blunted cells, results not being clear cut CD4 cells. Additionally, glutamine, processed by substrate level phosphorylation is emerging role player expansion differentiation Th1, Th17, ϒδ plasmablasts. circulating leukocytes play acting bioenergetic biomarkers diseases such diabetes suggests may also be tool preclinical SLE. Therefore, characterization immune subsets collection data interventions essential. delineation tuning lead novel strategies treating metabolically demanding processes characteristic autoimmune

Language: Английский

Citations

12
New insight in treating autoimmune diseases by targeting autophagy DOI Creative Commons
Jiao Lyu,

Hongqian Zhang,

Chaoyang Wang

et al.

Autoimmunity, Journal Year: 2024, Volume and Issue: 57(1)

Published: May 13, 2024

Autophagy is a highly conserved biological process in eukaryotes, which degrades cellular misfolded proteins, damaged organelles and invasive pathogens the lysosome-dependent manner. Autoimmune diseases caused by genetic elements, environments aberrant immune responses severely impact patients' living quality even threaten life. Recently, numerous studies have reported autophagy can regulate responses, play an important role autoimmune diseases. In this review, we summarised features of autophagy-related genes, enumerated some genes involved diseases, further overviewed how to treat through targeting autophagy. Finally, outlooked prospect relieving curing pathway.

Language: Английский

Citations

4
Factors associated with immune responses to SARS-CoV-2 vaccination in autoimmune disease individuals DOI Creative Commons
Erik Anderson, Michael D. Powell, Emily Yang

et al.

JCI Insight, Journal Year: 2024, Volume and Issue: 9(13)

Published: June 4, 2024

Patients with autoimmune diseases are at higher risk for severe infection due to their underlying disease and immunosuppressive treatments. In this real-world observational study of 463 subjects, we examined factors poor B T cell responses SARS-CoV-2 vaccination. We show a high frequency inadequate anti-spike IgG vaccination boosting in the population but minimal suppression responses. Low cell–depleted multiple sclerosis (MS) subjects were associated CD8 By contrast, taking mycophenolate mofetil exhibited concordant Treatments highest low response included depletion within last year, fingolimod, combination treatment (MMF) belimumab. Our data that mRNA-1273 (Moderna) vaccine, is most effective vaccine population. There was induction either flares or autoantibodies by no significant effect pre-existing anti-type I interferon antibodies on breakthrough infections. The infections lack SARS-CoV-2–related deaths suggest immunity contributes protection disease.

Language: Английский

Citations

4
Cytomegalovirus reactivation is frequent in multiple myeloma patients treated with daratumumab‐based regimens DOI Creative Commons
Danilo De Novellis,

Raffaele Fontana,

Bianca Serio

et al.

Cancer Medicine, Journal Year: 2024, Volume and Issue: 13(14)

Published: July 1, 2024

Abstract Background Viral reactivations are frequent in hematologial patients due to their cancer‐related and drug‐induced immunosuppressive status. Daratumumab, an anti‐CD38 monoclonal antibody, is used for multiple myeloma (MM) treatment, causes immunosuppression by targeting CD38‐expressing normal lymphocytes. In this single‐center two‐arm real‐life experience, we evaluated incidence of cytomegalovirus (CMV) reactivation MM treated with daratumumab‐based regimens as first‐ or second‐line therapy. Methods A total 101 consecutive were included study divided into two cohorts: daratumumab nondaratumumab‐based (control) regimens. Patients >2 lines therapies excluded reduce the confounding factor multi‐treated cases. Primary endpoint was CMV rate. Results rate significantly higher cohort compared control group (33% vs. 4%; p < 0.001), also CMV‐DNA levels (>1000 UI/mL 12% cases; 0.05). However, only one subject developed a disease severe pneumonia, while successfully preemptive therapy valganciclovir. No subjects required anti‐CMV agents ( = 0.02). Conclusion Our retrospective experience showed that might increase risk MM, currently underestimated related morbility mortality under treatments. further validation on larger prospective clinical trials required.

Language: Английский

Citations

4
Expanding scope of TEMRA in autoimmunity DOI Creative Commons
András Perl, Laurence Morel

EBioMedicine, Journal Year: 2023, Volume and Issue: 90, P. 104520 - 104520

Published: March 10, 2023

Language: Английский

Citations

10
Lower circulating mitochondrial DNA and increased mitokines suggest significant mitochondrial dysfunction in systemic lupus erythematosus with renal involvement DOI Creative Commons
Matthieu Halfon, Ashfaque A. Memon,

Anna Hedelius

et al.

Lupus Science & Medicine, Journal Year: 2025, Volume and Issue: 12(1), P. e001368 - e001368

Published: Feb. 1, 2025

Background SLE is associated with significant morbidity, especially in the case of renal involvement. Mitochondrial dysfunction plays a role and may be assessed by measuring mitochondrial DNA (mtDNA) cytokines reflecting stress (mitokines). Circulating mtDNA promising biomarker appears to reduced severe SLE. However, circulating challenging reported methods are heterogenous. Our study aimed at evaluating whole blood nuclear (nucDNA) ratio using droplet-digital PCR mitokines, growth differentiation factor 15 (GDF-15) fibroblast 21 without Methods Cross-sectional involving 195 patients age-matched healthy volunteers (HV) as control. Biomarkers were compared involvement (defined estimated glomerular filtration rate <60 mL/min or proteinuria >0.5 g/day) those active inactive Results Compared HV, displayed lower mtDNA/nucDNA ratios, Accordingly, mitokines increased We found no correlation between global disease activity. Mitokine levels, on other hand, correlated activity, particular GDF-15 even after adjusting for Conclusion findings suggest that ratio, surrogate marker dysfunction, reflects damage, while also reflect activity Further studies needed assess clinical value these markers predictors lupus nephritis.

Language: Английский

Citations

0
CD38 deficiency leads to a defective short-lived transcriptomic response to chronic graft-versus-host disease induction, involving purinergic signaling-related genes and distinct transcriptomic signatures associated with lupus DOI Creative Commons

Mercedes Zubiaur,

Laura C. Terrón‐Camero,

Fernando Gordillo-González

et al.

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 10, 2025

This study aimed to elucidate the transcriptomic signatures and dysregulated pathways associated with autoimmune response in Cd38 -/- mice compared wild-type (WT) within bm12 chronic graft-versus-host disease (cGVHD) lupus model. We conducted bulk RNA sequencing on peritoneal exudate cells (PECs) spleen (SPC) at two four weeks following adoptive cell transfer. also analyzed from healthy, untreated mice. These analyses revealed a sustained upregulation of transcriptional profile purinergic receptors ectonucleotidases cGVHD WT PECs, which displayed coordinated expression several type I interferon-stimulated genes (ISGs) key molecules involved cyclic GMP-AMP synthase-stimulator interferon (cGAS-STING) signaling pathway, hallmarks pathology. A second receptor profile, included P2rx7 P2rx4 , showed gene components NLRP3 inflammasome its potential activators. processes were transcriptionally less active PECs than PECs. have shown evidence distinct enrichment that define such as Ca 2+ ion homeostasis, division, phagosome, autophagy, senescence, cytokine/cytokine interactions, Th17 Th1/Th2 differentiation versus samples, reflected milder inflammatory elicited relative counterparts allogeneic challenge. Last, we an intense metabolic reprogramming toward oxidative phosphorylation SPC mice, may reflect increased cellular demand for oxygen consumption, contrast short-lived effect level. Overall, these findings support pro-inflammatory immunomodulatory role CD38 during development cGVHD-lupus disease.

Language: Английский

Citations

0