Immune Cell Profiling of Peripheral Blood as Signature for Response During Checkpoint Inhibition Across Cancer Types

Despite encouraging results with immune checkpoint inhibition (ICI), a large fraction of cancer patients still does not achieve clinical benefit. Finding predictive markers in the complexity of the tumor microenvironment is a challenging task and often requires invasive procedures. In our study, we looked for putative variables related to treatment benefit among immune cells in peripheral blood across different tumor types treated with ICIs. For that, we included 33 patients with different solid tumors referred to our clinical unit for ICI. Peripheral blood mononuclear cells were isolated at baseline, 6 and 20 weeks after treatment start. Characterization of immune cells was carried out by multi-color flow cytometry. Response to treatment was assessed radiologically by RECIST 1.1. Clinical outcome correlated with a shift towards an effector-like T cell phenotype, PD-1 expression by CD8+T cells, low levels of myeloid-derived suppressor cells and classical monocytes. Dendritic cells seemed also to play a role in terms of survival. From these findings, we hypothesized that patients responding to ICI had already at baseline an immune profile, here called ‘favorable immune periphery’, providing a higher chance of benefitting from ICI. We elaborated an index comprising cell types mentioned above. This signature correlated positively with the likelihood of benefiting from the treatment and ultimately with longer survival. Our study illustrates that patients responding to ICI seem to have a pre-existing immune profile in peripheral blood that favors good outcome. Exploring this signature can help to identify patients likely to achieve benefit from ICI.

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Expression of CYP24A1 and other multiple sclerosis risk genes in peripheral blood indicates response to vitamin D in homeostatic and inflammatory conditions

Genes and Immunity ◽

10.1038/s41435-021-00144-6 ◽

2021 ◽

Author(s):

Samantha P. L. Law ◽

Prudence N. Gatt ◽

Stephen D. Schibeci ◽

Fiona C. McKay ◽

Steve Vucic ◽

...

Keyword(s):

Multiple Sclerosis ◽

Vitamin D ◽

Immune Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Immunological Response ◽

Response To Treatment ◽

Peripheral Blood Mononuclear ◽

Risk Genes ◽

Inflammatory Models

AbstractAlthough genetic and epidemiological evidence indicates vitamin D insufficiency contributes to multiple sclerosis (MS), and serum levels of vitamin D increase on treatment with cholecalciferol, recent metanalyses indicate that this vitamin D form does not ameliorate disease. Genetic variation in genes regulating vitamin D, and regulated by vitamin D, affect MS risk. We evaluated if the expression of vitamin D responsive MS risk genes could be used to assess vitamin D response in immune cells. Peripheral blood mononuclear cells (PBMCs) were isolated from healthy controls and people with MS treated with dimethyl fumarate. We assayed changes in expression of vitamin D responsive MS risk (VDRMS) genes in response to treatment with 25 hydroxy vitamin D in the presence or absence of inflammatory stimuli. Expression of CYP24A1 and other VDRMS genes was significantly altered in PBMCs treated with vitamin D in the homeostatic and inflammatory models. Gene expression in MS samples had similar responses to controls, but lower initial expression of the risk genes. Vitamin D treatment abrogated these differences. Expression of CYP24A1 and other MS risk genes in blood immune cells indicate vitamin D response and could enable assessment of immunological response to vitamin D in clinical trials and on therapy.

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Single cell resolution landscape of equine peripheral blood mononuclear cells reveals diverse immune cell subtypes including T-bet+ B cells

10.1101/2020.05.05.077362 ◽

2020 ◽

Cited By ~ 1

Author(s):

Roosheel S. Patel ◽

Joy E. Tomlinson ◽

Thomas J. Divers ◽

Gerlinde R. Van de Walle ◽

Brad R. Rosenberg

Keyword(s):

B Cells ◽

Immune Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Immune Cell ◽

Model Organisms ◽

Traditional Model ◽

Cell Type ◽

Peripheral Blood Mononuclear ◽

Blood Mononuclear Cells

ABSTRACTTraditional laboratory model organisms represent a small fraction of the diversity of multicellular life, and findings in any given experimental model often do not translate to other species. Immunology research in non-traditional model organisms can be advantageous or even necessary (e.g. for host-pathogen interaction studies), but presents multiple challenges, many stemming from an incomplete understanding of potentially species-specific immune cell types, frequencies and phenotypes. Identifying and characterizing immune cells in such organisms is frequently limited by the availability of species-reactive immunophenotyping reagents for flow cytometry, and insufficient prior knowledge of cell type-defining markers. Here, we demonstrate the utility of single cell RNA sequencing (scRNA-Seq) to characterize immune cells for which traditional experimental tools are limited. Specifically, we used scRNA-Seq to comprehensively define the cellular diversity of equine peripheral blood mononuclear cells (PBMCs) from healthy horses across different breeds, ages, and sexes. We identified 30 cell type clusters partitioned into five major populations: Monocytes/Dendritic Cells, B cells, CD3+PRF1+ lymphocytes, CD3+PRF1- lymphocytes, and Basophils. Comparative analyses revealed many cell populations analogous to human PBMC, including transcriptionally heterogeneous monocytes and distinct dendritic cell subsets (cDC1, cDC2, plasmacytoid DC). Unexpectedly, we found that a majority of the equine peripheral B cell compartment is comprised of T-bet+ B cells; an immune cell subpopulation typically associated with chronic infection and inflammation in human and mouse. Taken together, our results demonstrate the potential of scRNA-Seq for cellular analyses in non-traditional model organisms, and form the basis for an immune cell atlas of horse peripheral blood.

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Analysis of human glioma-associated co-inhibitory immune checkpoints in glioma microenvironment and peripheral blood

International Journal of Immunopathology and Pharmacology ◽

10.1177/20587384211056505 ◽

2021 ◽

Vol 35 ◽

pp. 205873842110565

Author(s):

Shaoping Shen ◽

Qiyan Wu ◽

Jialin Liu ◽

Liangliang Wu ◽

Rong Zhang ◽

...

Keyword(s):

Immune Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Immune Cell ◽

Checkpoint Inhibitors ◽

Myeloid Cell ◽

Immune Checkpoints ◽

Human Glioma ◽

Peripheral Blood Mononuclear ◽

Glioma Microenvironment

One biomarker for a better therapeutic effect of immune checkpoint inhibitors is high expression of checkpoint in tumor microenvironment The purpose of this study is to investigate the expression of immune checkpoints in human glioma microenvironment and peripheral blood mononuclear cells. First, single-cell suspension from 20 fresh high-grade glioma (HGG) specimens were obtained, and analyzed for lymphocyte composition, then six co-inhibitory immune checkpoints were analyzed at the same time. Second, 36 PBMC specimens isolated from HGG blood samples were analyzed for the same items. In GME, there were four distinct subtypes of cells, among them, immune cells accounted for an average of 51.3%. The myeloid cell population (CD11b+) was the most common immune cell identified, accounting for 36.14% on average; the remaining were most CD3+CD4+ and CD3+/CD8−/CD4− T lymphocytes. In these cells, we detected the expression of BTLA, LAG3, Tim-3, CTLA-4, and VISTA on varying degrees. While in PBMCs, the result showed that when compared with healthy volunteers, the proportion of NK cells decreased significantly in HGG samples ( p < 0.01). Moreover, the expression of BTLA, LAG3, and Tim-3 in CD45+ immune cells in PBMC was more remarkable in glioma samples. In conclusion, the CD11b+ myeloid cells were the predominant immune cells in GME. Moreover, some immune checkpoints displayed a more remarkable expression on the immune cells in GME. And the profile of checkpoint expression in PBMC was partially consistent with that in GME.

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671 Biological impacts of standard of care chemotherapies on immune effector cells from AML patients

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.671 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A699-A699

Author(s):

Dmitry Zhigarev ◽

Alexander MacFarlane ◽

Christina Drenberg ◽

Reza Nejati ◽

Asya Varshavsky ◽

...

Keyword(s):

Nk Cells ◽

Immune Cells ◽

Immune Cell ◽

Cell Phenotype ◽

Second Line ◽

Color Flow ◽

Immune Effector ◽

Effector Cells ◽

Immune Effector Cells ◽

And Function

BackgroundAcute myeloid leukemia (AML) is a heterogeneous group of malignant bone marrow diseases, characterized by massive and uncontrolled proliferation of myeloid precursor cells, which alters normal blood cell ratios. This disease is common to older adults and collectively displays one of the lowest 5-year overall survival rates (<25%) among all cancers, currently representing the deadliest form of leukemia. Improved treatments are clearly needed, and immunotherapies are attractive candidate therapies to explore.There are currently several standard chemotherapeutic treatment schemes for AML, which could be divided into two major groups: (1) cytotoxic chemotherapy (“7+3” or daunorubicin-cytarabine) and (2) hypomethylating agents (HMAs). HMAs include both 5-azacytidine and decitabine, which are cytidine analogs that inhibit DNA methyltransferase, resulting in the hypomethylation of DNA and inducing expression of silenced gene loci. Currently, HMAs are routinely delivered in combination with the Bcl-2 inhibitor venetoclax.The goals of this study are to determine how these standard first line therapies can affect the frequency and functional integrity of effector immune cells in patients' blood and establish when the phenotype and function of immune cells are restored to identify time windows when second line immunotherapies could be most effective.MethodsMore than 100 blood samples were obtained from 33 previously untreated AML patients. More than 50 measurable biomarkers were analyzed using 14-color flow cytometry to assess immune phenotypes of T and NK cells in peripheral blood of AML patients prior to treatment and at up to four timepoints after initiation of treatment with HMA or chemotherapy.ResultsWe found several significant changes in immune cell phenotype and function that occur in response to these therapies. Treatment with HMAs was strikingly less impactful on immune cells in patients compared to previously published in vitro studies. Nevertheless, HMA treatment increased perforin levels in T and NK cells, inhibited IFN-gamma secretion by CD8+ T cells, and changed expression of several checkpoint molecules. While chemotherapy caused fewer phenotypic changes it dramatically decreased the total number of immune cells. We also determined viable, functional and phenotypical recovery periods for immune effector cells after the treatments.ConclusionsOur results are important for introducing new second line immunotherapies to these chemotherapeutic regimens for treating AML and to improve overall understanding of immune cell behavior under conditions of anti-tumor treatment.AcknowledgementsSupported by grants from Janssen and the U.S./Israel Binational Science Foundation.Ethics ApprovalThe study was approved by the Fox Chase Cancer Center Institutional Review Board, approval number 17-8010, and all patients provided informed consent before taking part in the study.

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Abnormal B-Cell and Tfh-Cell Profiles in Patients With Parkinson Disease

Neurology Neuroimmunology & Neuroinflammation ◽

10.1212/nxi.0000000000001125 ◽

2021 ◽

Vol 9 (2) ◽

pp. e1125

Author(s):

Rui Li ◽

Thomas Francis Tropea ◽

Laura Rosa Baratta ◽

Leah Zuroff ◽

Maria E. Diaz-Ortiz ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

Parkinson Disease ◽

B Cell ◽

Immune Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Immune Cell ◽

Ex Vivo ◽

Cell Counts

Background and ObjectivesThere has been growing interest in potential roles of the immune system in the pathogenesis of Parkinson disease (PD). The aim of the current study was to comprehensively characterize phenotypic and functional profiles of circulating immune cells in patients with PD vs controls.MethodsPeripheral blood was collected from patients with PD and age- and sex-matched neurologically normal controls (NCs) in 2 independent cohorts (discovery and validation). Comprehensive multicolor flow cytometry was performed on whole blood leukocytes and peripheral blood mononuclear cells to characterize different immune subsets and their ex vivo responses.ResultsThe discovery cohort included 17 NCs and 12 participants with PD, and the validation cohort included 18 NCs and 18 participants with PD. Among major immune cell types, B cells appeared to be preferentially affected in PD. Proliferating B cell counts were decreased in patients with PD compared with controls. Proportions of B-cell subsets with regulatory capacity such as transitional B cells were preferentially reduced in the patients with PD, whereas proportions of proinflammatory cytokine-producing B cells increased, resulting in a proinflammatory shift of their B-cell functional cytokine responses. Unsupervised principal component analysis revealed increased expression of TNFα and GM-CSF by both B cells and T cells of patients with PD. In addition, levels of follicular T cells, an important B-cell helper T-cell population, decreased in the patients with PD, correlating with their B-cell abnormality.DiscussionOur findings define a novel signature of peripheral immune cells and implicate aberrant Tfh:B-cell interactions in patients with PD.

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Immune Cell Landscape of Patients With Diabetic Macular Edema by Single-Cell RNA Analysis

Frontiers in Pharmacology ◽

10.3389/fphar.2021.754933 ◽

2021 ◽

Vol 12 ◽

Author(s):

Pengjuan Ma ◽

Ping Zhang ◽

Shuxia Chen ◽

Wen Shi ◽

Jinguo Ye ◽

...

Keyword(s):

Macular Edema ◽

Single Cell ◽

Differential Expression ◽

Signaling Pathway ◽

Diabetic Macular Edema ◽

Immune Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Immune Cell ◽

Differential Expression Analysis

Purpose: We performed single-cell RNA sequencing (scRNA-seq), an unbiased and high-throughput single cell technology, to determine phenotype and function of peripheral immune cells in patients with diabetic macular edema (DME).Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from DME patients and healthy controls (HC). The single-cell samples were loaded on the Chromium platform (10x Genomics) for sequencing. R package Seurat v3 was used for data normalizing, clustering, dimensionality reduction, differential expression analysis, and visualization.Results: We constructed a single-cell RNA atlas comprising 57,650 PBMCs (24,919 HC, 32,731 DME). We divided all immune cells into five major immune cell lineages, including monocytes (MC), T cells (TC), NK cells (NK), B cells (BC), and dendritic cells (DC). Our differential expression gene (DEG) analysis showed that MC was enriched of genes participating in the cytokine pathway and inflammation activation. We further subdivided MC into five subsets: resting CD14++ MC, proinflammatory CD14++ MC, intermediate MC, resting CD16++ MC and pro-inflammatory CD16++ MC. Remarkably, we revealed that the proinflammatory CD14++ monocytes predominated in promoting inflammation, mainly by increasingly production of inflammatory cytokines (TNF, IL1B, and NFKBIA) and chemokines (CCL3, CCL3L1, CCL4L2, CXCL2, and CXCL8). Gene Ontology (GO) and pathway analysis of the DEGs demonstrated that the proinflammatory CD14++ monocytes, especially in DME patients, upregulated inflammatory pathways including tumor necrosis factor-mediated signaling pathway, I-kappaB kinase/NF-kappaB signaling, and toll-like receptor signaling pathway.Conclusion: In this study, we construct the first immune landscape of DME patients with T2D and confirmed innate immune dysregulation in peripheral blood based on an unbiased scRNA-seq approach. And these results demonstrate potential target cell population for anti-inflammation treatments.

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The immune cell landscape of peripheral blood mononuclear cells from PNS patients

Scientific Reports ◽

10.1038/s41598-021-92573-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Qing Ye ◽

Chao Zhou ◽

Sisi Li ◽

Jingjing Wang ◽

Fei Liu ◽

...

Keyword(s):

T Cells ◽

Nephrotic Syndrome ◽

B Cells ◽

Nk Cells ◽

Cd8 T Cells ◽

Immune Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Immune Cell ◽

Immunological Mechanism

AbstractExisting research suggests that the human immune system and immune cells are involved in the pathogenesis of nephrotic syndrome, but there is still a lack of direct evidence. This study tried to analyze the profiling of immune cells in the peripheral blood of steroid-sensitive nephrotic syndrome (SSNS) patients and steroid-resistant nephrotic syndrome (SRNS) patients before and after standard steroid treatment to clarify the immunological mechanism of nephrotic syndrome patients. The number and proportion of CD4 + T cells in patients with nephrotic syndrome remained unchanged. However, there is an imbalance of Th1 and Th2 and an excessive increase of Th17 cells. The number of CD8 + T cells and the number of effector CD8 + T cells in them increased significantly, but only in SSNS, the number of activated CD8 + T cells increased, and the number of activated Treg cells decreased significantly. Nephrotic syndrome patients also have B cell disorder, and it is more prominent in SSNS patients. Compared with the normal control, only the number of B cells and plasmablast in SSNS patients increased significantly (Z = − 2.20, P = 0.028). This study also observed that transitional B cells decreased in both SSNS and SRNS patients, but SSNS patients' decrease was lower than in SRNS patients. Compared with normal controls, monocytes in patients with nephrotic syndrome decreased significantly. The main reason was that Non-classical Monocyte decreased, while Classical Monocyte increased slightly. The total number of NK cells did not change, but the internal cell subgroups' composition occurred. Changes, realized as CD56hi NK cells increased, CD56low NK cells decreased; and the above trend is more evident in SSNS patients. Patients with nephrotic syndrome have immune disorders, including T cells, B cells, Monocytes, and NK cells. It can be confirmed that immune factors are involved in the pathogenesis of the nephrotic syndrome.

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Single-cell resolution landscape of equine peripheral blood mononuclear cells reveals diverse cell types including T-bet+ B cells

BMC Biology ◽

10.1186/s12915-020-00947-5 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Roosheel S. Patel ◽

Joy E. Tomlinson ◽

Thomas J. Divers ◽

Gerlinde R. Van de Walle ◽

Brad R. Rosenberg

Keyword(s):

B Cells ◽

Immune Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Immune Cell ◽

Cell Types ◽

Model Organisms ◽

Traditional Model ◽

Cell Type ◽

Peripheral Blood Mononuclear

Abstract Background Traditional laboratory model organisms represent a small fraction of the diversity of multicellular life, and findings in any given experimental model often do not translate to other species. Immunology research in non-traditional model organisms can be advantageous or even necessary, such as when studying host-pathogen interactions. However, such research presents multiple challenges, many stemming from an incomplete understanding of potentially species-specific immune cell types, frequencies, and phenotypes. Identifying and characterizing immune cells in such organisms is frequently limited by the availability of species-reactive immunophenotyping reagents for flow cytometry, and insufficient prior knowledge of cell type-defining markers. Results Here, we demonstrate the utility of single-cell RNA sequencing (scRNA-Seq) to characterize immune cells for which traditional experimental tools are limited. Specifically, we used scRNA-Seq to comprehensively define the cellular diversity of equine peripheral blood mononuclear cells (PBMC) from healthy horses across different breeds, ages, and sexes. We identified 30 cell type clusters partitioned into five major populations: monocytes/dendritic cells, B cells, CD3+PRF1+ lymphocytes, CD3+PRF1− lymphocytes, and basophils. Comparative analyses revealed many cell populations analogous to human PBMC, including transcriptionally heterogeneous monocytes and distinct dendritic cell subsets (cDC1, cDC2, plasmacytoid DC). Remarkably, we found that a majority of the equine peripheral B cell compartment is comprised of T-bet+ B cells, an immune cell subpopulation typically associated with chronic infection and inflammation in human and mouse. Conclusions Taken together, our results demonstrate the potential of scRNA-Seq for cellular analyses in non-traditional model organisms and form the basis for an immune cell atlas of horse peripheral blood.

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34 Selective infiltration of Antibody-Dependent Cellular Cytoxicity (ADCC) mediating immune cells in response to treatment in a human tumor histo-culture platform

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.034 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A40-A40

Author(s):

Satish Sankaran ◽

Nandini Pal Basak ◽

Sindhu Govindan ◽

BV Prakash ◽

BV Manjula ◽

...

Keyword(s):

Nk Cells ◽

Immune Cells ◽

Peripheral Blood ◽

Immune Cell ◽

Nk Cell ◽

Granzyme B ◽

Human Tumor ◽

Neutrophil Infiltration ◽

Fold Change ◽

Response To Treatment

BackgroundA 3D histo-culture platform provides a near native Tumor immune Micro-Environment (TiME), making it best suited for evaluating response to immunotherapy drugs. Farcast™ TiME is a human 3D tumor histo-culture platform that preserves TiME and maintains functional fidelity of intra-tumoral immune cells (IIC). In this study we investigated the utility of this platform in demonstrating treatment induced Antibody-Dependent Cellular Cytotoxicity (ADCC) mechanism driven by IICs alone versus co-culture with autologous peripheral blood immune cells.MethodsHead and neck squamous cell carcinoma tissue samples (n=5) along with matched blood from consented patients were used in this study. All Peripheral Blood Nucleated Cells (PBNCs) including lymphocytes, monocytes, NK cells and neutrophils were isolated and stained with a tracking dye to distinguish them from IICs. Tumor tissues were processed to generate explants, treated with 184 µg/ml Cetuximab (anti-EGFR) or vehicle control, and cultured with or without PBNCs for 72 hrs. Response was evaluated using flow cytometry and cytokine release assay.ResultsAmount of infiltrated autologous PBNCs showed a strong negative correlation (R2=0.98) with the amount of IICs in the absence of drug treatment. The proportions of infiltrated immune cell sub-populations were similar to the composition of PBNCs added in culture. Cetuximab treatment, however, led to enhanced infiltration of the effector cells for ADCC driven tumor killing, namely NK cells, macrophages, neutrophils, and cytotoxic T cells (CTLs). Notably the unique infiltration pattern of effector cell populations observed in each sample was reflected in the secretion of specific cytokine/chemokines associated with that cell population. NK cell increase (fold change: 1.6 ± 0.8) was observed in all samples with a concomitant increase in MCP-1 secretion (fold change: 1.7 ± 0.9). Granzyme-B expressing NK cells increased (>1.7 fold) in a subset of samples. Samples showing increase in neutrophil infiltration exhibited increased MMP9 secretion, involved in neutrophil infiltration via stromal remodeling. Sample with highest increase in infiltration of CD16+ Monocyte/Macrophages (>2.4 fold) showed maximum increase in Granzyme-B secretion with respect to the untreated arm. Increase in fold secretion (>1.4) of CXCL9/CXCL10 was associated with the sample that showed highest fold increase of Granzyme-B expressing CTL in comparison to untreated arm. IICs alone were not sufficient in eliciting optimal ADCC response.ConclusionsThe study demonstrated ADCC response in the explant/PBNC co-culture platform leading to specific infiltration of effector sub-populations. FarcastTM TiME thus provides a unique platform to explore for heterologous adoptive cell and CAR-T therapies that involve immune cell infiltration.Ethics ApprovalAll samples included in the study were approved by institutional review boards of the centers providing the samples.

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Activation of immune cell proteasomes in peripheral blood of smokers and COPD patients - implications for therapy

European Respiratory Journal ◽

10.1183/13993003.01798-2021 ◽

2021 ◽

pp. 2101798

Author(s):

Ilona E. Kammerl ◽

Sophie Hardy ◽

Claudia Flexeder ◽

Andrea Urmann ◽

Julia Peierl ◽

...

Keyword(s):

Immune Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Immune Cell ◽

Young Male ◽

Peripheral Blood Mononuclear ◽

Therapeutic Concept ◽

Copd Patients ◽

Native Gel

Immune cells contain a specialised type of proteasome, i.e. the immunoproteasome, which is required for intracellular protein degradation. Immunoproteasomes are key regulators of immune cell differentiation, inflammatory activation and autoimmunity. Immunoproteasome function in peripheral immune cells might be altered by smoking and in COPD thereby affecting immune cell responses.We here analysed the expression and activity of proteasome complexes in peripheral blood mononuclear cells (PBMC) isolated from healthy male young smokers as well as from patients with severe COPD and compared them to matching controls. Proteasome expression was upregulated in COPD patients as assessed by RT-qPCR and mass spectrometry-based proteomics analysis. Proteasome activity was quantified using activity-based probes and native gel analysis. We observed distinct activation of immunoproteasomes in the peripheral blood cells of young male smokers and severely ill COPD patients. Native gel analysis and linear regression modeling confirmed robust activation and elevated assembly of 20S proteasomes, which correlated significantly with reduced lung function parameters in COPD patients. The immunoproteasome was distinctly activated in COPD patients upon inflammatory cytokine stimulation of PBMCs in vitro. Inhibition of the immunoproteasome reduced proinflammatory cytokine expression in COPD-derived blood immune cells.Given the crucial role of chronic inflammatory signalling and the emerging involvement of autoimmune responses in COPD, therapeutic targeting of the immunoproteasome might represent a novel therapeutic concept for COPD.

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