Integrative Analysis of Minichromosome Maintenance Proteins and Their Prognostic Significance in Melanoma

BackgroundMinichromosome maintenance (MCM) is known for participating in cell cycle progression, as well as DNA replication. While the diverse expression patterns and prognostic values of MCMs in melanoma still remained unclear.MethodsIn the present study, the transcriptional and clinical profiles of MCMs were explored in patients with melanoma from multiple databases, including GEO, TCGA, ONCOMINE, GEPIA, UALCAN, cBioPortal, and TIMER databases.ResultsWe found that the elevated expressions of MCM2–6 and MCM10 were significantly expressed in melanoma compared to normal skin. High mRNA levels of MCM4, MCM5, and MCM10 were closely related to worse prognosis in patients with melanoma. GSEA showed hallmark pathways were most involved in mTORC1 signaling, G2M checkpoint, E2F targets, and mitotic spindle. Furthermore, we found potential correlations between the MCM expression and the immune cell infiltration, including B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells.ConclusionUpregulated MCM gene expression in melanoma probably played a crucial part in the development and progression of melanoma. The upregulated MCM4/5/10 expressions could be used as potential prognostic markers to improve the poor outcome and prognostic accuracy in patients with melanoma. Our study might shed light on the selection of prognostic biomarkers as well as the underlying molecular pathogenesis of melanoma.

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Single Cell Profiling Reveals Unique CXCL13 Positive T Cell Subsets in the Tumor Microenvironment of Lymphocyte Rich Classic Hodgkin Lymphoma

Blood ◽

10.1182/blood-2020-134929 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 32-33

Author(s):

Tomohiro Aoki ◽

Lauren C. Chong ◽

Katsuyoshi Takata ◽

Katy Milne ◽

Elizabeth Chavez ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

Single Cell ◽

Immune Cells ◽

Research Funding ◽

Immune Cell ◽

Expression Patterns ◽

The Other ◽

Tfh Cells

Introduction: Classic Hodgkin lymphoma (CHL) features a unique crosstalk between malignant cells and different types of normal immune cells in the tumor-microenvironment (TME). On the basis of histomorphologic and immunophenotypic features of the malignant Hodgkin and Reed-Sternberg (HRS) cells and infiltrating immune cells, four histological subtypes of CHL are recognized: Nodular sclerosing (NS), Mixed cellularity, Lymphocyte-rich (LR) and Lymphocyte-depleted CHL. Recently, our group described the high abundance of various types of immunosuppressive CD4+ T cells including LAG3+ and/or CTLA4+ cells in the TME of CHL using single cell RNA sequencing (scRNAseq). However, the TME of LR-CHL has not been well characterized due to the rarity of the disease. In this study, we aimed at characterizing the immune cell profile of LR-CHL at single cell resolution. METHODS: We performed scRNAseq on cell suspensions collected from lymph nodes of 28 primary CHL patients, including 11 NS, 9 MC and 8 LR samples, with 5 reactive lymph nodes (RLN) serving as normal controls. We merged the expression data from all cells (CHL and RLN) and performed batch correction and normalization. We also performed single- and multi-color immunohistochemistry (IHC) on tissue microarray (TMA) slides from the same patients. In addition, an independent validation cohort of 31 pre-treatment LR-CHL samples assembled on a TMA, were also evaluated by IHC. Results: A total of 23 phenotypic cell clusters were identified using unsupervised clustering (PhenoGraph). We assigned each cluster to a cell type based on the expression of genes described in published transcriptome data of sorted immune cells and known canonical markers. While most immune cell phenotypes were present in all pathological subtypes, we observed a lower abundance of regulatory T cells (Tregs) in LR-CHL in comparison to the other CHL subtypes. Conversely, we found that B cells were enriched in LR-CHL when compared to the other subtypes and specifically, all four naïve B-cell clusters were quantitatively dominated by cells derived from the LR-CHL samples. T follicular helper (TFH) cells support antibody response and differentiation of B cells. Our data show the preferential enrichment of TFH in LR-CHL as compared to other CHL subtypes, but TFH cells were still less frequent compared to RLN. Of note, Chemokine C-X-C motif ligand 13 (CXCL13) was identified as the most up-regulated gene in LR compared to RLN. CXCL13, which is a ligand of C-X-C motif receptor 5 (CXCR5) is well known as a B-cell attractant via the CXCR5-CXCL13 axis. Analyzing co-expression patterns on the single cell level revealed that the majority of CXCL13+ T cells co-expressed PD-1 and ICOS, which is known as a universal TFH marker, but co-expression of CXCR5, another common TFH marker, was variable. Notably, classical TFH cells co-expressing CXCR5 and PD-1 were significantly enriched in RLN, whereas PD-1+ CXCL13+ CXCR5- CD4+ T cells were significantly enriched in LR-CHL. These co-expression patterns were validated using flow cytometry. Moreover, the expression of CXCR5 on naïve B cells in the TME was increased in LR-CHL compared to the other CHL subtypes We next sought to understand the spatial relationship between CXCL13+ T cells and malignant HRS cells. IHC of all cases revealed that CXCL13+ T cells were significantly enriched in the LR-CHL TME compared to other subtypes of CHL, and 46% of the LR-CHL cases showed CXCL13+ T cell rosettes closely surrounding HRS cells. Since PD-1+ T cell rosettes are known as a specific feature of LR-CHL, we confirmed co-expression of PD-1 in the rosetting cells by IHC in these cases. Conclusions: Our results reveal a unique TME composition in LR-CHL. LR-CHL seems to be distinctly characterized among the CHL subtypes by enrichment of CXCR5+ naïve B cells and CD4+ CXCL13+ PD-1+ T cells, indicating the importance of the CXCR5-CXCL13 axis in the pathogenesis of LR-CHL. Figure Disclosures Savage: BeiGene: Other: Steering Committee; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie: Honoraria; Roche (institutional): Research Funding; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie, Servier: Consultancy. Scott:Janssen: Consultancy, Research Funding; Celgene: Consultancy; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoString, Research Funding; NIH: Consultancy, Other: Co-inventor on a patent related to the MCL35 assay filed at the National Institutes of Health, United States of America.; Roche/Genentech: Research Funding; Abbvie: Consultancy; AstraZeneca: Consultancy. Steidl:AbbVie: Consultancy; Roche: Consultancy; Curis Inc: Consultancy; Juno Therapeutics: Consultancy; Bayer: Consultancy; Seattle Genetics: Consultancy; Bristol-Myers Squibb: Research Funding.

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Prognostic Interactions between FAP+ Fibroblasts and CD8a+ T Cells in Colon Cancer

Cancers ◽

10.3390/cancers12113238 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3238

Author(s):

Mercedes Herrera ◽

Artur Mezheyeuski ◽

Lisa Villabona ◽

Sara Corvigno ◽

Carina Strell ◽

...

Keyword(s):

Colon Cancer ◽

T Cells ◽

Immune Cell ◽

Therapeutic Potential ◽

Immune Surveillance ◽

Prognostic Significance ◽

Experimental Studies ◽

Population Based ◽

Good Prognosis ◽

High Group

Inter-case variations in immune cell and fibroblast composition are associated with prognosis in solid tumors, including colon cancer. A series of experimental studies suggest immune-modulatory roles of marker-defined fibroblast populations, including FAP-positive fibroblasts. These studies imply that the fibroblast status of tumors might affect the prognostic significance of immune-related features. Analyses of a population-based colon cancer cohort demonstrated good prognosis associations of FAP intensity and CD8a density. Notably, a significant prognostic interaction was detected between these markers (p = 0.013 in nonadjusted analyses and p = 0.003 in analyses adjusted for cofounding factors) in a manner where the good prognosis association of CD8 density was restricted to the FAP intensity-high group. This prognostic interaction was also detected in an independent randomized trial-derived colon cancer cohort (p = 0.048 in nonadjusted analyses). In the CD8-high group, FAP intensity was significantly associated with a higher total tumor density of FoxP3-positive immune cells and a higher ratio of epithelial-to-stromal density of CD8a T cells. The study presents findings relevant for the ongoing efforts to improve the prognostic performance of CD8-related markers and should be followed by additional validation studies. Furthermore, findings support, in general, earlier model-derived studies implying fibroblast subsets as clinically relevant modulators of immune surveillance. Finally, the associations between FAP intensity and specific immune features suggest mechanisms of fibroblast-immune crosstalk with therapeutic potential.

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Altered Expression of Three EGFR Posttranslational Regulators MDGI, MIG6, and EIG121 in Invasive Breast Carcinomas

Analytical Cellular Pathology ◽

10.1155/2020/9268236 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Didier Meseure ◽

Kinan Drak Alsibai ◽

Sophie Vacher ◽

Rana Hatem ◽

Andre Nicolas ◽

...

Keyword(s):

Expression Patterns ◽

Prognostic Significance ◽

Growth Factor Receptor ◽

Growth Inhibitor ◽

Receptor Activation ◽

Mrna Levels ◽

Breast Carcinomas ◽

Rt Pcr ◽

Altered Expression ◽

Invasive Breast Carcinomas

Epidermal growth factor receptor (EGFR) signalling is a highly regulated process with a tight balance between receptor activation and inactivation in invasive breast carcinomas (IBCs) particularly in triple-negative carcinomas (TNC). Clinical trials using anti-EGFR therapies are actually performed although no activating alterations (mutations, amplifications, or rearrangements) of EGFR have been clearly recognized in order to identify new targeted modalities for IBCs. We explored mammary-derived growth inhibitor (MDGI), estrogen-induced gene-121 (EIG121), and mitogen-induced gene-6 (MIG6), three posttranslational EGFR trafficking molecules implicated in EGFR spatiotemporal regulatory pathway. We quantified MDGI, EIG121, and MIG6 at mRNA levels by using real-time quantitative RT-PCR in a series of 440 IBCs and at protein levels by using immunohistochemistry in a series of 88 IBCs. Results obtained by RT-PCR showed that in IBCs, MDGI, MIG6, and EIG121 mRNA were mainly underexpressed (25.7%, 45.0%, and 16.1%, respectively) particularly in the TNC subtype for EIG121 (60.3%). We also observed mRNA overexpression of MDGI and EIG121, respectively, in 12.7% and 22.3% of IBCs. These altered mRNA expressions were confirmed at the protein level. Some links were found between expression patterns of these three genes and several classical pathological and clinical parameters. Only EIG121 was found to have a prognostic significance (p=0.0038). Altered expression of these three major EGFR posttranslational negative regulators could create an aberrant EGFR-mediated oncogenic signalling pathway in IBCs. MDGI, MIG6, and EIG121 expression status also may be potential useful biomarkers (sensitivity or resistance) in targeted EGFR therapy.

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Reduced polyfunctional T cells and increased cellular activation markers in adult allergy patients reporting adverse reactions to food

10.21203/rs.2.23606/v1 ◽

2020 ◽

Author(s):

Friederike Sonnet ◽

Ellen Namork ◽

Eva Stylianou ◽

Ingvild Gaare-Olstad ◽

Kanutte Huse ◽

...

Keyword(s):

T Cells ◽

Adverse Reactions ◽

Mononuclear Cells ◽

Immune Cell ◽

Expression Patterns ◽

Adult Patients ◽

Cell Populations ◽

Functional Markers ◽

Peripheral Blood Mononuclear ◽

Activation Markers

Abstract Background: The underlying cellular mechanisms causing adverse reactions to food are complex and still not fully understood. Therefore, in this study we aimed to identify functional and/or phenotypical immune cell signatures characteristic for adult patients reporting adverse reactions to food. By mass cytometry, we performed high-dimensional profiling of peripheral blood mononuclear cells (PBMC) from adult patients reporting adverse reactions to food and healthy controls. The patients were grouped according to sIgE-positive or sIgE-negative serology to common food and inhalant allergens. Two broad antibody panels were used, allowing determination of major immune cell populations in PBMC, as well as activation status, proliferation status, and cytokine expression patterns after PMA/ionomycin-stimulation on a single cell level. Results: By use of data-driven algorithms, several cell populations were identified showing significantly different marker expression between the groups. Most striking was an impaired frequency and function of polyfunctional CD4 + and CD8 + T cells in patients reporting adverse reactions to food compared to the controls. Further, subpopulations of monocytes, T cells, and B cells had increased expression of functional markers such as CD371, CD69, CD25, CD28, and/or HLA-DR as well as decreased expression of CD23 in the patients. Most of the differing cell subpopulations were similarly altered in the two subgroups of patients. Conclusion: Our results suggest common immune cell features for both patient subgroups reporting adverse reactions to food, and provide a basis for further studies on mechanistic and diagnostic biomarker studies in food allergy.

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The Serine Protease CD26/DPP4 in Non-Transformed and Malignant T Cells

Cancers ◽

10.3390/cancers13235947 ◽

2021 ◽

Vol 13 (23) ◽

pp. 5947

Author(s):

Guranda Chitadze ◽

Ulrike Wehkamp ◽

Ottmar Janssen ◽

Monika Brüggemann ◽

Marcus Lettau

Keyword(s):

T Cells ◽

T Cell ◽

Serine Protease ◽

T Cell Activation ◽

Cell Activation ◽

Immune Cell ◽

Transmembrane Protein ◽

Expression Patterns ◽

Soluble Form ◽

Interaction Partners

CD26/Dipeptidylpeptidase 4 is a transmembrane serine protease that cleaves off N-terminal dipeptides. CD26/DPP4 is expressed on several immune cell types including T and NK cells, dendritic cells, and activated B cells. A catalytically active soluble form of CD26/DPP4 can be released from the plasma membrane. Given its wide array of substrates and interaction partners CD26/DPP4 has been implicated in numerous biological processes and effects can be dependent or independent of its enzymatic activity and are exerted by the transmembrane protein and/or the soluble form. CD26/DPP4 has been implicated in the modulation of T-cell activation and proliferation and CD26/DPP4-positive T cells are characterized by remarkable anti-tumor properties rendering them interesting candidates for T cell-based immunotherapies. Moreover, especially in cutaneous T-cell lymphoma CD26/DPP4 expression patterns emerged as an established marker for diagnosis and treatment monitoring. Surprisingly, besides a profound knowledge on substrates, interaction partners, and associated signal transduction pathways, the precise role of CD26/DPP4 for T cell-based immune responses is only partially understood.

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Prognostic Biomarkers and Therapeutic Targets Identification Among CXC Chemokines in the Colon Adenocarcinoma Microenvironment

10.21203/rs.3.rs-1213978/v1 ◽

2022 ◽

Author(s):

Heng Wang ◽

ChangQing Guo ◽

Jun Luo ◽

Quan Li ◽

BuQing Fu ◽

...

Keyword(s):

T Cells ◽

Immune Cell ◽

Prognostic Significance ◽

Cell Activity ◽

Colon Adenocarcinoma ◽

Prognostic Indicators ◽

Chemokine Signaling ◽

High Incidence ◽

High Incidence Rate ◽

Chemokine Signaling Pathway

Abstract Background: COAD is among the most prevalent malignancy, with a very high incidence rate. Crosstalk between cancer and interstitial cells significantly affects cancer development, modulated partly by chemokines production. When present in the tumor microenvironment, CXC chemokines have been shown to regulate tumor cell activity and influence immune cell transport, resulting in anti-tumor immune mechanisms and influencing the outcomes of the patient; nonetheless, the CXC chemokines expression levels in COAD, as well as their prognostic significance, have not yet been established.Methods: This study used UALCAN, GeneMANIA, STRING, TRRUST, cBioPortal, TIMER, and GEPIA,Results: The expression of CXC1/2/3/5/6/11/12/13/14/16/17 in COAD patients was shown to be significantly correlated with the pathological stage. A considerably improved prognosis was observed in patients with low transcriptional levels of CXCL9/10/11. Differentially expressed CXC chemokines exert roles that are predominantly correlated with the chemokine signaling pathway and interactions of cytokine–cytokine receptors. Our findings indicated that the transcriptional factors, including SP1, RELA, and NFKB1 are essential for the production of CXC chemokines. Furthermore, we discovered a substantial association between the CXC chemokines production and infiltration of 6 kinds of immune cells (CD8+ T cells, dendritic cells, B cells, CD4+ T cells, neutrophils, and macrophages,). Conclusions: These findings might be useful in identifying prognostic indicators and immunotherapeutic targets for colon cancer.

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Effects of IFN-B on TRAIL and Decoy Receptor Expression in Different Immune Cell Populations from MS Patients with Distinct Disease Subtypes

Autoimmune Diseases ◽

10.4061/2011/485752 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Andrea L. O. Hebb ◽

Craig S. Moore ◽

Virender Bhan ◽

George S. Robertson

Keyword(s):

T Cells ◽

Neutralizing Antibodies ◽

Immune Cell ◽

Surrogate Marker ◽

Normal Subjects ◽

Receptor Expression ◽

Mrna Levels ◽

Decoy Receptor ◽

Relapsing Remitting ◽

Distinct Disease

Using quantitative RT-PCR, we compared mRNA levels for TRAIL [tumor necrosis factor (TNF)–related apoptosis-inducing ligand] and its receptors in various immune cell subsets derived from the peripheral blood of untreated normal subjects (NS) and patients with distinct subtypes of multiple sclerosis (MS): active relapsing-remitting MS (RRA), quiescent relapsing-remitting MS (RRQ), secondary-progressive MS (SPMS) or primary-progressive MS (PPMS). Consistent with a role for TRAIL in the mechanism of action of interferon-β (IFN-β), TRAIL mRNA levels were increased in monocytes from patients clinically responsive to IFN-β (RRQ) but not those unresponsive to this therapeutic (RRA). TRAIL-R3 (decoy receptor) expression was elevated in T cells from untreated RRMS patients while IFN-β therapy reversed this increase suggesting that IFN-β may promote the apoptotic elimination of autoreactive T cells by increasing the amount of TRAIL available to activate TRAIL death receptors. Serum concentrations of soluble TRAIL were increased to a similar extent by IFN-β therapy in RRQ, RRA and SPMS patients that had not generated neutralizing antibodies against this cytokine. Although our findings suggest altered TRAIL signaling may play a role in MS pathogenesis and IFN-β therapy, they do not support use of TRAIL as a surrogate marker for clinical responsiveness to this therapeutic.

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Correlation between tumor infiltrating immune cells and peripheral regulatory T cell determined using methylation analyses and its prognostic significance in resected gastric cancer

PLoS ONE ◽

10.1371/journal.pone.0252480 ◽

2021 ◽

Vol 16 (6) ◽

pp. e0252480

Author(s):

Koung Jin Suh ◽

Jin Won Kim ◽

Ji Eun Kim ◽

Ji Hea Sung ◽

Jiwon Koh ◽

...

Keyword(s):

Gastric Cancer ◽

T Cells ◽

T Cell ◽

Cell Density ◽

Immune Cell ◽

Prognostic Significance ◽

Disease Free Survival ◽

Prognostic Information ◽

Curative Surgery ◽

Cd4 Cell

Peripheral regulatory T cells (pTregs) are a highly immunosuppressive fraction of CD4+ T cells. We aimed to evaluate the clinical significance of pTregs in patients with gastric cancer and to determine the correlation between pTregs and immune cell infiltration in tumor microenvironment. pTregs status was determined by assessing the pTreg/total T-cell ratio (ratio of Foxp3 Treg-specific demethylated region (TSDR) to CD3G/CD3D demethylation, so-called Cellular Ratio of Immune Tolerance “ImmunoCRIT”) using methylation analyses in 433 patients with gastric cancer who received curative surgery. Among 422 evaluable patients, 230 (54.5%) had high ImmunoCRIT (> 21.0). Patients with high ImmunoCRIT had significantly shorter disease-free survival (DFS) and overall survival (OS) than those with high ImmunoCRIT (p = 0.030, p = 0.008, respectively). In multivariate analysis, high ImmunoCRIT kept a prognostic role for shorter OS (hazard ratio [HR] 1.9, 95% confidence interval [CI] 1.4–2.9; p = 0.005). CD3+ cell density and CD4+ cell density was significantly higher within the tumor in high ImmunoCRIT group than those in low ImmunoCRIT group (CD3+ cell, 202.12/mm2 vs. 172.2/mm2, p = 0.029; CD4+ cell, 56.5/mm2 vs. 43.5/mm2, p = 0.007). In conclusion, the peripheral ImmunoCRIT determined by epigenetic methylation analysis provides prognostic information in resected gastric tumors.

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Type I Interferon Response Identified through Phenotypic and Transcriptional Profiling of Circulating Immune Cells during Idiopathic Multicentric Castleman Disease Flare

Blood ◽

10.1182/blood-2019-128994 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1046-1046 ◽

Cited By ~ 1

Author(s):

Ruth-Anne Langan ◽

Alberto Japp ◽

Michael Gonzalez ◽

Rozena Rasheed ◽

Sheila K Pierson ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Immune Cell ◽

Nk Cell ◽

Castleman Disease ◽

Type I ◽

Gene Set ◽

Healthy Donors ◽

Mtorc1 Signaling

Idiopathic multicentric Castleman disease (iMCD) is a rare hematologic illness involving episodic disease flares with polyclonal cytokine-induced lymphoproliferation, systemic inflammation, and life-threatening multi-organ dysfunction. iMCD is further classified by clinical features and the most severe cases of iMCD often fall into the thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin myelofibrosis, renal dysfunction, and organomegaly (TAFRO) clinical subtype. A cytokine storm involving interleukin(IL)-6 drives disease pathogenesis in a subset of patients, however only 34% of patients were found to respond to anti-IL-6 therapy with siltuximab in its registrational clinical trial. The identification of next generation therapeutics for iMCD-TAFRO patients has been challenging as the etiology, pathological cell types, and signaling pathways involved in iMCD-TAFRO are largely unknown. In this study, we aimed to identify cellular drivers and pathophysiological mechanisms of iMCD-TAFRO through the use of an unbiased multi-omics approach. We obtained paired bulk peripheral blood mononuclear cells (PBMCs) from a cohort of ten iMCD-TAFRO patients isolated during disease flare and clinical remission. These paired PBMC samples were utilized for flow cytometry to assess immune cell frequency and phenotype between iMCD-TAFRO flare and remission as well as between flare and age/sex matched healthy donors (n = 10). Three paired iMCD-TAFRO samples were also selected for transcriptional profiling using single-cell RNA sequencing (scRNAseq). We observed phenotypic differences across the T cell, monocyte, and NK cell compartments. We observed a significant increase in the frequency of CD8 T cells within the T cell compartment as well as an increased frequency of granzyme B and perforin expressing CD8 T cells in iMCD-TAFRO flare compared to healthy donors. We also observed a significant increase in the frequency of CD56+ NK cells within the NK cell compartment and a significant increase in the frequency of CD14+ monocytes within the monocyte compartment during iMCD-TAFRO flare compared to healthy donors. Together, these data suggest activation and involvement of CD8 T cell, NK cell, and monocyte subsets during iMCD-TAFRO flare. We next utilized Gene Set Enrichment Analysis (GSEA) of our single-cell transcriptomics dataset to ask whether circulating immune cell frequencies display enrichment of the 50 Hallmark gene sets during flare compared to remission across three iMCD-TAFRO patients. We found significant enrichment (FDR < 0.01) of genes within the Interferon Alpha Response gene set in circulating non-naïve CD8 T cells, classical monocytes, nonclassical monocytes, NK cells, and dendritic cells. These data suggest that a number of circulating immune cell populations may be responding to Type I interferon (IFN-I) during iMCD-TAFRO flare. In addition, our group has recently reported mTORC1 activation in iMCD and has characterized in three iMCD-TAFRO patients a clinical response following mTOR inhibition with sirolimus. Within our scRNAseq dataset, we identified mTORC1 signaling to be enriched only in circulating classical and nonclassical monocytes during flare. Having observed enrichment of both the Interferon Alpha Response Gene set and the mTORC1 signaling gene set in circulating monocytes, we then asked whether the relative expression of IFN-I response genes and mTORC1 signaling genes are correlated within circulating classical and nonclassical monocytes. Indeed, we observed a significant positive correlation between the average relative expression of mTORC1 signaling genes and IFN-I Response genes across classical, but not nonclassical, monocytes from all three iMCD-TAFRO patients (all R2 ≥0.6, p<0.0001).These data suggest a potential link between IFN-I signaling and mTORC1 signaling activation in classical monocytes in iMCD-TAFRO flare. Following further characterization of this association, we propose investigation into the use of Janus kinase (JAK) inhibitors in iMCD, as JAK is a proximal signaling molecule downstream of the IFN-alpha/beta receptor (IFNAR) and upstream of mTORC1 signaling. In summary, this dataset demonstrates involvement of multiple immune cell populations and identifies IFN-I signaling as a novel inflammatory gene program that may contribute to iMCD-TAFRO pathogenesis and drive treatment identification. Disclosures van Rhee: Takeda: Consultancy; Sanofi Genzyme: Consultancy; Castleman Disease Collaborative Network: Consultancy; EUSA: Consultancy; Adicet Bio: Consultancy; Kite Pharma: Consultancy; Karyopharm Therapeutics: Consultancy. Fajgenbaum:Janssen Pharmaceuticals: Research Funding.

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Reduced polyfunctional T cells and increased cellular activation markers in adult allergy patients reporting adverse reactions to food

10.21203/rs.2.23606/v2 ◽

2020 ◽

Author(s):

Friederike Sonnet ◽

Ellen Namork ◽

Eva Stylianou ◽

Ingvild Gaare-Olstad ◽

Kanutte Huse ◽

...

Keyword(s):

T Cells ◽

Adverse Reactions ◽

Mononuclear Cells ◽

Immune Cell ◽

Expression Patterns ◽

Cell Populations ◽

Functional Markers ◽

Cellular Mechanisms ◽

Peripheral Blood Mononuclear ◽

Activation Markers

Abstract Background: The underlying cellular mechanisms causing adverse reactions to food are complex and still not fullyunderstood. Therefore, in this study we aimed to identify functional and/or phenotypical immune cell signaturescharacteristic for adult patients reporting adverse reactions to food.By mass cytometry, we performed high-dimensional profiling of peripheral blood mononuclear cells (PBMC) fromadult patients reporting adverse reactions to food and healthy controls. The patients were grouped according to sIgE-positive or sIgE-negative serology to common food and inhalant allergens. Two broad antibody panels were used,allowing determination of major immune cell populations in PBMC, as well as activation status, proliferation status,and cytokine expression patterns after PMA/ionomycin-stimulation on a single cell level.Results: By use of data-driven algorithms, several cell populations were identified showing significantly differentmarker expression between the groups.Most striking was an impaired frequency and function of polyfunctional CD4+ and CD8+ T cells in patients reportingadverse reactions to food compared to the controls. Further, subpopulations of monocytes, T cells, and B cells hadincreased expression of functional markers such as CD371, CD69, CD25, CD28, and/or HLA-DR as well asdecreased expression of CD23 in the patients. Most of the differing cell subpopulations were similarly altered in thetwo subgroups of patients.Conclusion: Our results suggest common immune cell features for both patient subgroups reporting adversereactions to food, and provide a basis for further studies on mechanistic and diagnostic biomarker studies in foodallergy.

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