scholarly journals IL17A critically shapes the transcriptional program of fibroblasts in pancreatic cancer and switches on their protumorigenic functions

2021 ◽  
Vol 118 (6) ◽  
pp. e2020395118
Author(s):  
Gianluca Mucciolo ◽  
Claudia Curcio ◽  
Cecilia Roux ◽  
Wanda Y. Li ◽  
Michela Capello ◽  
...  
Keyword(s):  
T Cells ◽  
Messenger Rna ◽  
Cell Transformation ◽  
Ductal Adenocarcinoma ◽  
Matrix Remodeling ◽  
T Helper 1 ◽  
Cell Recruitment ◽  
Desmoplastic Reaction ◽  
Neoplastic Cell Transformation

A hallmark of cancer, including pancreatic ductal adenocarcinoma (PDA), is a massive stromal and inflammatory reaction. Many efforts have been made to identify the anti- or protumoral role of cytokines and immune subpopulations within the stroma. Here, we investigated the role of interleukin-17A (IL17A) and its effect on tumor fibroblasts and the tumor microenvironment. We used a spontaneous PDA mouse model (KPC) crossed to IL17A knockout mice to show an extensive desmoplastic reaction, without impaired immune infiltration. Macrophages, especially CD80+ and T cells, were more abundant at the earlier time point. In T cells, a decrease in FoxP3+ cells and an increase in CD8+ T cells were observed in KPC/IL17A−/− mice. Fibroblasts isolated from IL17A+/+ and IL17A−/− KPC mice revealed very different messenger RNA (mRNA) and protein profiles. IL17A−/− fibroblasts displayed the ability to restrain tumor cell invasion by producing factors involved in extracellular matrix remodeling, increasing T cell recruitment, and producing higher levels of cytokines and chemokines favoring T helper 1 cell recruitment and activation and lower levels of those recruiting myeloid/granulocytic immune cells. Single-cell quantitative PCR on isolated fibroblasts confirmed a very divergent profile of IL17A-proficient and -deficient cells. All these features can be ascribed to increased levels of IL17F observed in the sera of IL17A−/− mice, and to the higher expression of its cognate receptor (IL17RC) specifically in IL17A−/− cancer-associated fibroblasts (CAFs). In addition to the known effects on neoplastic cell transformation, the IL17 cytokine family uniquely affects fibroblasts, representing a suitable candidate target for combinatorial immune-based therapies in PDA.

scholarly journals The Dynamic Interaction between Extracellular Matrix Remodeling and Breast Tumor Progression

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1046
Author(s):  
Jorge Martinez ◽  
Patricio C. Smith
Keyword(s):  
Extracellular Matrix ◽  
Type I Collagen ◽  
Cell Metabolism ◽  
Breast Tumors ◽  
Extracellular Matrix Remodeling ◽  
Type I ◽  
Matrix Remodeling ◽  
Desmoplastic Reaction ◽  
The Impact

Desmoplastic tumors correspond to a unique tissue structure characterized by the abnormal deposition of extracellular matrix. Breast tumors are a typical example of this type of lesion, a property that allows its palpation and early detection. Fibrillar type I collagen is a major component of tumor desmoplasia and its accumulation is causally linked to tumor cell survival and metastasis. For many years, the desmoplastic phenomenon was considered to be a reaction and response of the host tissue against tumor cells and, accordingly, designated as “desmoplastic reaction”. This notion has been challenged in the last decades when desmoplastic tissue was detected in breast tissue in the absence of tumor. This finding suggests that desmoplasia is a preexisting condition that stimulates the development of a malignant phenotype. With this perspective, in the present review, we analyze the role of extracellular matrix remodeling in the development of the desmoplastic response. Importantly, during the discussion, we also analyze the impact of obesity and cell metabolism as critical drivers of tissue remodeling during the development of desmoplasia. New knowledge derived from the dynamic remodeling of the extracellular matrix may lead to novel targets of interest for early diagnosis or therapy in the context of breast tumors.

scholarly journals m6A demethylase ALKBH5 controls CD4+ T cell pathogenicity and promotes autoimmunity

2021 ◽  
Vol 7 (25) ◽  
pp. eabg0470
Author(s):  
Jing Zhou ◽  
Xingli Zhang ◽  
Jiajia Hu ◽  
Rihao Qu ◽  
Zhibin Yu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Messenger Rna ◽  
Interferon Γ ◽  
Autoimmune Encephalomyelitis ◽  
Cell Responses ◽  
Chemokine Ligand ◽  
The Central Nervous System ◽  
Chemokine Ligand 2

N6-methyladenosine (m6A) modification is dynamically regulated by “writer” and “eraser” enzymes. m6A “writers” have been shown to ensure the homeostasis of CD4+ T cells, but the “erasers” functioning in T cells is poorly understood. Here, we reported that m6A eraser AlkB homolog 5 (ALKBH5), but not FTO, maintains the ability of naïve CD4+ T cells to induce adoptive transfer colitis. In addition, T cell–specific ablation of ALKBH5 confers protection against experimental autoimmune encephalomyelitis. During the induced neuroinflammation, ALKBH5 deficiency increased m6A modification on interferon-γ and C-X-C motif chemokine ligand 2 messenger RNA (mRNA), thus decreasing their mRNA stability and protein expression in CD4+ T cells. These modifications resulted in attenuated CD4+ T cell responses and diminished recruitment of neutrophils into the central nervous system. Our findings reveal an unexpected specific role of ALKBH5 as an m6A eraser in controlling the pathogenicity of CD4+ T cells during autoimmunity.

scholarly journals T-bet represses collagen-induced arthritis by suppressing Th17 lineage commitment through inhibition of RORγt expression and function

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Masaru Shimizu ◽  
Yuya Kondo ◽  
Reona Tanimura ◽  
Kotona Furuyama ◽  
Masahiro Yokosawa ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
T Helper 1 ◽  
Collagen Induced Arthritis ◽  
Over Expression ◽  
Th17 Differentiation ◽  
And Function ◽  
Arthritic Joints

AbstractT-bet is a key transcription factor for the T helper 1 lineage and its expression level is negatively correlated to inflammation in patients with rheumatoid arthritis (RA). Our previous study using T-bet transgenic mice revealed over-expression of T-bet completely suppressed collagen-induced arthritis (CIA), a murine model of RA, indicating a potential suppressive role of T-bet in the pathogenesis of autoimmune arthritis. Here, we show T-bet-deficiency exacerbated CIA. T-bet in CD4 + T cells, but not in CD11c + dendritic cells, was critical for regulating the production of IL-17A, IL-17F, IL-22, and TNFα from CD4 + T cells. T-bet-deficient CD4 + T cells showed higher RORγt expression and increased IL-17A production in RORγt-positive cells after CII immunization. In addition, T-bet-deficient naïve CD4 + T cells showed accelerated Th17 differentiation in vitro. CIA induced in CD4-Cre T-betfl/fl (cKO) mice was more severe and T-bet-deficient CD4 + T cells in the arthritic joints of cKO mice showed higher RORγt expression and increased IL-17A production. Transcriptome analysis of T-bet-deficient CD4 + T cells revealed that expression levels of Th17-related genes were selectively increased. Our results indicate that T-bet in CD4 + T cells repressed RORγt expression and function resulting in suppression of arthritogenic Th17 cells and CIA.

scholarly journals p53 functional impairment and high p21waf1/cip1 expression in human T- cell lymphotropic/leukemia virus type I-transformed T cells

Blood ◽  
1996 ◽  
Vol 88 (5) ◽  
pp. 1551-1560 ◽  
Author(s):  
A Cereseto ◽  
F Diella ◽  
JC Mulloy ◽  
A Cara ◽  
P Michieli ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Virus Type ◽  
Cell Transformation ◽  
Leukemia Virus ◽  
Type I ◽  
Wild Type ◽  
Human T Cell ◽  
Wild Type P53

Abstract Human T-cell lymphotropic/leukemia virus type I (HTLV-I) is associated with T-cell transformation both in vivo and in vitro. Although some of the mechanisms responsible for transformation remain unknown, increasing evidence supports a direct role of viral as well as dysregulated cellular proteins in transformation. We investigated the potential role of the tumor suppressor gene p53 and of the p53- regulated gene, p21waf1/cip1 (wild-type p53 activated fragment 1/cycling dependent kinases [cdks] interacting protein 1), in HTLV-I- infected T cells. We have found that the majority of HTLV-I-infected T cells have the wild-type p53 gene. However, its function in HTLV-I- transformed cells appears to be impaired, as shown by the lack of appropriate p53-mediated responses to ionizing radiation (IR). Interestingly, the expression of the p53 inducible gene, p21waf1/cip1, is elevated at the messenger ribonucleic acid and protein levels in all HTLV-I-infected T-cell lines examined as well as in Taxl-1, a human T- cell line stably expressing Tax. Additionally, Tax induces upregulation of a p21waf1/cip1 promoter-driven luciferase gene in p53 null cells, and increases p21waf1/cip1 expression in Jurkat T cells. These findings suggest that the Tax protein is at least partially responsible for the p53-independent expression of p21waf1/cip1 in HTLV-I-infected cells. Dysregulation of p53 and p21waf1/cip1 proteins regulating cell-cycle progression, may represent an important step in HTLV-I-induced T-cell transformation.

scholarly journals p53 functional impairment and high p21waf1/cip1 expression in human T- cell lymphotropic/leukemia virus type I-transformed T cells

Blood ◽  
1996 ◽  
Vol 88 (5) ◽  
pp. 1551-1560 ◽  
Author(s):  
A Cereseto ◽  
F Diella ◽  
JC Mulloy ◽  
A Cara ◽  
P Michieli ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Virus Type ◽  
Cell Transformation ◽  
Leukemia Virus ◽  
Type I ◽  
Wild Type ◽  
Human T Cell ◽  
Wild Type P53

Human T-cell lymphotropic/leukemia virus type I (HTLV-I) is associated with T-cell transformation both in vivo and in vitro. Although some of the mechanisms responsible for transformation remain unknown, increasing evidence supports a direct role of viral as well as dysregulated cellular proteins in transformation. We investigated the potential role of the tumor suppressor gene p53 and of the p53- regulated gene, p21waf1/cip1 (wild-type p53 activated fragment 1/cycling dependent kinases [cdks] interacting protein 1), in HTLV-I- infected T cells. We have found that the majority of HTLV-I-infected T cells have the wild-type p53 gene. However, its function in HTLV-I- transformed cells appears to be impaired, as shown by the lack of appropriate p53-mediated responses to ionizing radiation (IR). Interestingly, the expression of the p53 inducible gene, p21waf1/cip1, is elevated at the messenger ribonucleic acid and protein levels in all HTLV-I-infected T-cell lines examined as well as in Taxl-1, a human T- cell line stably expressing Tax. Additionally, Tax induces upregulation of a p21waf1/cip1 promoter-driven luciferase gene in p53 null cells, and increases p21waf1/cip1 expression in Jurkat T cells. These findings suggest that the Tax protein is at least partially responsible for the p53-independent expression of p21waf1/cip1 in HTLV-I-infected cells. Dysregulation of p53 and p21waf1/cip1 proteins regulating cell-cycle progression, may represent an important step in HTLV-I-induced T-cell transformation.

scholarly journals ICAMs Redistributed by Chemokines to Cellular Uropods as a Mechanism for Recruitment of T Lymphocytes

1997 ◽  
Vol 137 (2) ◽  
pp. 493-508 ◽  
Author(s):  
Miguel Angel del Pozo ◽  
Carlos Cabañas ◽  
María C. Montoya ◽  
Ann Ager ◽  
Paloma Sánchez-Mateos ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Fold Increase ◽  
Time Lapse ◽  
Cell Recruitment ◽  
T Cell Migration ◽  
Physiological Relevance ◽  
Amplification System

The recruitment of leukocytes from the bloodstream is a key step in the inflammatory reaction, and chemokines are among the main regulators of this process. During lymphocyte–endothelial interaction, chemokines induce the polarization of T lymphocytes, with the formation of a cytoplasmic projection (uropod) and redistribution of several adhesion molecules (ICAM-1,-3, CD43, CD44) to this structure. Although it has been reported that these cytokines regulate the adhesive state of integrins in leukocytes, their precise mechanisms of chemoattraction remain to be elucidated. We have herein studied the functional role of the lymphocyte uropod. Confocal microscopy studies clearly showed that cell uropods project away from the cell bodies of adhered lymphocytes and that polarized T cells contact other T cells through the uropod structure. Time-lapse videomicroscopy studies revealed that uropod-bearing T cells were able, through this cellular projection, to contact, capture, and transport additional bystander T cells. Quantitative analysis revealed that the induction of uropods results in a 5–10-fold increase in cell recruitment. Uropod-mediated cell recruitment seems to have physiological relevance, since it was promoted by both CD45R0+ peripheral blood memory T cells as well as by in vivo activated lymphocytes. Additional studies showed that the cell recruitment mediated by uropods was abrogated with antibodies to ICAM-1, -3, and LFA-1, whereas mAb to CD43, CD44, CD45, and L-selectin did not have a significant effect, thus indicating that the interaction of LFA-1 with ICAM-1 and -3 appears to be responsible for this process. To determine whether the increment in cell recruitment mediated by uropod may affect the transendothelial migration of T cells, we carried out chemotaxis assays through confluent monolayers of endothelial cells specialized in lymphocyte extravasation. An enhancement of T cell migration was observed under conditions of uropod formation, and this increase was prevented by incubation with either blocking anti– ICAM-3 mAbs or drugs that impair uropod formation. These data indicate that the cell interactions mediated by cell uropods represent a cooperative mechanism in lymphocyte recruitment, which may act as an amplification system in the inflammatory response.

scholarly journals OP0136 RITUXIMAB PREVENTS THE PROGRESSION OF B-CELL DRIVEN INFLAMMATORY INFILTRATE IN THE MINOR SALIVARY GLANDS OF PRIMARY SJOGREN’S SYNDROME BY DOWNREGULATING IMMUNOLOGICAL PATHWAYS KEY IN ECTOPIC GERMINAL CENTRE ORGANIZATION: RESULTS FROM THE TRACTISS TRIAL

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 79-80
Author(s):  
E. Pontarini ◽  
F. Chowdhury ◽  
E. Sciacca ◽  
S. Grigoriadou ◽  
F. Rivellese ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Histological Analysis ◽  
Immune Cell ◽  
Salivary Flow ◽  
Memory B Cells ◽  
Cell Recruitment ◽  
Immune Cell Recruitment

Background:The pathogenic role of B-cells in primary Sjögren’s Syndrome (pSS) is well established and B cell abnormalities. Because of the substantial role of B-cells, rituximab (RTX), a chimeric anti-CD20 monoclonal antibody, has been considered as a potential biologic disease modifying drug to reduce disease activity in pSS. To date, the TRial for Anti-B-Cell Therapy In patients with pSS (TRACTISS) is the largest multi-centre, placebo-controlled trial with RTX. Despite the unmet primary endpoints (30% reduction in fatigue or oral dryness, measured by visual analogue scale), RTX treated patients showed an improvement in unstimulated whole salivary flow (Bowman et al. Arthritis Rheumatol 2017;69:1440–1450).Objectives:To provide the first longitudinal transcriptomic and histological analysis at 3 time points over 48 weeks of labial SGs of pSS patients treated with RTX, in comparison to placebo, from the TRACTISS cohort.Methods:26 pSS patients randomised to RTX or placebo arm consented for labial SG biopsies at baseline, weeks 16 and 48. Patients received two 1000mg cycles of RTX or placebo at baseline and week 24. SG focus score, inflammatory aggregate area fraction, B-cells (CD20+), T-cells (CD3+), follicular dendritic cells (FDCs) (CD21+) and plasma cells (CD138+) density were assessed by H&E and immunofluorescence staining. The histological analysis was performed by digital imaging using QuPath software. RNA was extracted from matched labial SG lobules and sequenced with Illumina platform. A Principal Component Analysis (PCA) and features driving the PCA were investigated along with the most influential gene loadings. The limma-voom R pipeline was used to extract Differential Expressed Genes (DEGs) between placebo and RTX group at week 48, and gene ontology (GO) enrichment analysis performed through EnrichR to derive GO terms and pathways associated with DEGs.Results:Placebo-treated labial SGs showed a worsening of inflammation highlighted by the increment of B-cell density, development of new FDC networks, and a higher ectopic GC prevalence at week 48, compared to RTX-treated patients. No difference in total T-cells and plasma cell infiltration was observed. RTX downregulated genes involved in immune cell recruitment and inflammatory aggregate organisation (e.g. CCR7, CCL19, CD52, and PDCD1) and gene signature-based analysis of 64 immune cell types highlighted how RTX preferentially blocked class-switched- and memory-B-cells infiltration in SGs at week 48. Pathway analyses confirmed the downregulation of leukocyte migration, MHC class II antigen presentation, and T-cell co-stimulation immunological pathways, such as the CD40 receptor complex pathway. The analysis of placebo SGs transcriptomic at week 48 showed a higher expression of genes linked to ectopic GC organisation, such as CXCL13, CCL19, LTβ, in female compared to male subjects. Gender was confirmed as a key co-variate responsible for most of the variation in the PCA, together with the SG focus score and the foci area fraction.Conclusion:Treatment with RTX showed beneficial effects on labial SG inflammatory infiltration in pSS, by downregulating genes involved in immune cell recruitment, activation and organisation in ectopic GCs. Class-switched-B-cells, memory-B-cells and FDC network development were primarily affected appearing to be responsible for the lack of progression in SG B cell infiltration in the RTX compared to the placebo arm in which clear worsening of SG immunopathology over 48 weeks was detected in female patients. Although a clear association with the clinical improvement in unstimulated salivary flow observed at week 48 in RTX-treated patients could not be established given the low number of patients consenting to 3 longitudinal biopsies it is conceivable that RTX is responsible for preserving exocrine function.Acknowledgements:SJB receives a salary contribution from the NIHR Birmingham Biomedical Research Centre.Disclosure of Interests:Elena Pontarini: None declared, Farzana Chowdhury: None declared, Elisabetta Sciacca: None declared, Sofia Grigoriadou: None declared, Felice Rivellese: None declared, Davide Lucchesi: None declared, Katriona Goldmann: None declared, Liliane Fossati-Jimack: None declared, Paul Emery: None declared, Wan Fai Ng: None declared, Nurhan Sutcliffe: None declared, Colin Everett: None declared, Catherine Fernandez: None declared, Anwar Tappuni: None declared, Myles Lewis: None declared, Costantino Pitzalis: None declared, Simon J. Bowman Consultant of: SJB In 2020 I have received consultancy fees from Novartis, Abbvie and Galapagos., Michele Bombardieri: None declared

scholarly journals Direct and Indirect Effect of TGFβ on Treg Transendothelial Recruitment in HCC Tissue Microenvironment

2021 ◽  
Vol 22 (21) ◽  
pp. 11765
Author(s):  
Francesco Dituri ◽  
Serena Mancarella ◽  
Grazia Serino ◽  
Nada Chaoul ◽  
Luigi Giovanni Lupo ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Cells ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Inverse Correlation ◽  
Transendothelial Migration ◽  
Desmoplastic Reaction ◽  
Tissue Microenvironment ◽  
Tgfβ Receptor

The balance between anti-tumor and tumor-promoting immune cells, such as CD4+ Th1 and regulatory T cells (Tregs), respectively, is assumed to dictate the progression of hepatocellular carcinoma (HCC). The transforming growth factor beta (TGFβ) markedly shapes the HCC microenvironment, regulating the activation state of multiple leukocyte subsets and driving the differentiation of cancer associated fibroblasts (CAFs). The fibrotic (desmoplastic) reaction in HCC tissue strongly depends on CAFs activity. In this study, we attempted to assess the role of TGFβ on transendothelial migration of Th1-oriented and Treg-oriented CD4+ T cells via a direct or indirect, CAF-mediated mechanisms, respectively. We found that the blockage of TGFβ receptor I-dependent signaling in Tregs resulted in impaired transendothelial migration (TEM) of these cells. Interestingly, the secretome of TGFβ-treated CAFs inhibited the TEM of Tregs but not Th1 cells, in comparison to the secretome of untreated CAFs. In addition, we found a significant inverse correlation between alpha-SMA and FoxP3 (marker of Tregs) mRNA expression in a microarray analysis involving 78 HCCs, thus suggesting that TGFβ-activated stromal cells may counteract the trafficking of Tregs into the tumor. The apparent dual behavior of TGFβ as both pro- and anti-tumorigenic cytokines may add a further level of complexity to the mechanisms that regulate the interactions among cancerous, stromal, and immune cells within HCC, as well as other solid tumors, and contribute to better manipulation of the TGFβ signaling as a therapeutic target in HCC patients.

scholarly journals The Role of Stellate Cells in Pancreatic Ductal Adenocarcinoma: Targeting Perspectives

2021 ◽  
Vol 10 ◽  
Author(s):  
Yang Wu ◽  
Chun Zhang ◽  
Kuirong Jiang ◽  
Jens Werner ◽  
Alexandr V. Bazhin ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Gastrointestinal Malignancy ◽  
Desmoplastic Reaction ◽  
Pancreatic Cancer Cells ◽  
Promising Strategy

Pancreatic ductal adenocarcinoma (PDAC) is a gastrointestinal malignancy with a dismal clinical outcome. Accumulating evidence suggests that activated pancreatic stellate cells (PSCs), the major producers of extracellular matrix (ECM), drive the severe stromal/desmoplastic reaction in PDAC. Furthermore, the crosstalk among PSCs, pancreatic cancer cells (PCCs) as well as other stroma cells can establish a growth-supportive tumor microenvironment (TME) of PDAC, thereby enhancing tumor growth, metastasis, and chemoresistance via various pathways. Recently, targeting stroma has emerged as a promising strategy for PDAC therapy, and several novel strategies have been proposed. The aim of our study is to give a profound review of the role of PSCs in PDAC progression and recent advances in stroma-targeting strategies.

Sign in / Sign up

Export Citation Format

Share Document