scholarly journals Intestinal Stem Cells and Immune Cell Relationships: Potential Therapeutic Targets for Inflammatory Bowel Diseases

2021 ◽  
Vol 11 ◽  
Author(s):  
Qihang Hou ◽  
Jingxi Huang ◽  
Hammed Ayansola ◽  
Hori Masatoshi ◽  
Bingkun Zhang
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Dendritic Cells ◽  
Immune Cells ◽  
Immune Cell ◽  
Clinical Symptoms ◽  
Chronic Inflammatory Disease ◽  
Intestinal Stem Cells ◽  
Inflammatory Bowel

The mammalian intestine is the largest immune organ that contains the intestinal stem cells (ISC), differentiated epithelial cells (enterocytes, Paneth cells, goblet cells, tuft cells, etc.), and gut resident-immune cells (T cells, B cells, dendritic cells, innate lymphoid cell, etc.). Inflammatory bowel disease (IBD), a chronic inflammatory disease characterized by mucosa damage and inflammation, threatens the integrity of the intestine. The continuous renewal and repair of intestinal mucosal epithelium after injury depend on ISCs. Inflamed mucosa healing could be a new target for the improvement of clinical symptoms, disease recurrence, and resection-free survival in IBD treated patients. The knowledge about the connections between ISC and immune cells is expanding with the development of in vitro intestinal organoid culture and single-cell RNA sequencing technology. Recent findings implicate that immune cells such as T cells, ILCs, dendritic cells, and macrophages and cytokines secreted by these cells are critical in the regeneration of ISCs and intestinal epithelium. Transplantation of ISC to the inflamed mucosa may be a new therapeutic approach to reconstruct the epithelial barrier in IBD. Considering the links between ISC and immune cells, we predict that the integration of biological agents and ISC transplantation will revolutionize the future therapy of IBD patients.

scholarly journals Key Immune Cell Subsets Are Dysregulated in Patients with Myelofibrosis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5580-5580
Author(s):  
Marco Romano ◽  
Lucia Catani ◽  
Daria Sollazzo ◽  
Martina Barone ◽  
Margherita Perricone ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Cells ◽  
Th17 Cells ◽  
Immune Cell ◽  
Opportunistic Infections ◽  
Fungal Infections ◽  
High Rate ◽  
Healthy Controls ◽  
Immune Cell Subsets

Abstract Introduction: Myelofibrosis (MF) is a clonal disorder associated mainly with JAK2V617F and MPL mutations. Recently, a new mutation in the gene encoding calreticulin (CALR) was discovered in the majority of JAK2/MPL negative patients. MF is burdened by a high rate of potentially life-threatening infections. The issue of recurrent and opportunistic infections is increased after the introduction in clinical practice of JAK inhibitors with immunosuppressive activity. However, the role of crucial immune cell subsets is still poorly characterized. Here, we investigated the phenotype/function of selected immune cells in MF. Specifically, we focused on circulating regulatory (Tregs) and IL-17-producing T cells (Th17 cells), monocytes and dendritic cells (DCs). Monocyte-derived DCs were also characterized. Methods: We characterized circulating Th17 cells, Tregs, monocytes and DCs of 17 untreated MF patients and 8 healthy controls (HC) by flow cytometry. Th17 cells were identified as CD4+ CD161+ CD196+ cells while Tregs were enumerated as CD4+ CD25high CD127low T cells. We also tested the in vitro suppressive activity of circulating CD4+ CD25+ Tregs with a mixed leukocyte reaction assay. Two subpopulations of circulating DCs, myeloid CD11c+ and plasmacytoid CD123+cells, were enumerated as well. In addition, after immunomagnetic selection, we tested both phenotype of circulating monocytes and their capacity to differentiate into CD14-derived immature and mature DCs, using a specific cytokines cocktail. JAK2V617F and MPL mutations were detected with RT-PCR while the presence of CALR mutations were tested with Exon 9 Next Generation Sequencing assay. Results: JAK2V617F (11 cases), MPL (3 cases), and CARL (3 cases) mutations were detected. We found that circulating CD4+CD25highCD127low Tregs were reduced in MF patients as compared with healthy controls (p=0.043), although their suppressive ability was maintained. We also found a lower number of circulating Th17 cells (p=0.0026) in MF patients. This finding was particularly evident in JAK2V617F+(p=0.008) and CARL+(p=0.03) patients. Despite their number was in the normal range, circulating monocytes from MF patients showed reduced expression of the CD86 co-stimulatory molecule. Moreover, as compared with the normal counterparts, immature monocytes-derived DCs from patients maintained low CD14 expression without upregulating the CD80 co-stimulatory molecule expression (p=0.0063). Interestingly, at variance with plasmacytoid DCs, a reduced number of circulating myeloid DCs was observed in MF patients as compared with that of HC (p=0.01). Conclusions: Here we demonstrated that specific crucial subsets of immune cells show quantitative and/or qualitative abnormalities in MF patients. These findings may be useful to better understand the increased susceptibility of these patients to infections, since Th17 cells play a role in bacterial and fungal infections while myeloid DCs regulate Th1 activity. Of note, DCs inhibition might result in increased propensity to infections and compromised immune response to cancer.In addition, since monocytes are DC precursors, alterations in their differentiation pathway may contribute to develop defective immune responses. Disclosures Martinelli: NOVARTIS: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; PFIZER: Consultancy; ARIAD: Consultancy.

Leukemic Dendritic Cells Expand Central Memory T Lymphocytes From HCT Donors Able to React against the Original Leukemia in Vitro and In Vivo.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4090-4090
Author(s):  
Monica Casucci ◽  
Serena Kimi Perna ◽  
Attilio Bondanza ◽  
Zulma Magnani ◽  
Massimo Bernardi ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Dendritic Cells ◽  
T Lymphocytes ◽  
Central Memory ◽  
Ionophore A23187 ◽  
Leukemic Stem Cells ◽  
Memory T Lymphocytes

Abstract Abstract 4090 Poster Board III-1025 Allogeneic hematopoietic transplantation (allo-HCT) is the only curative option for patients affected by high-risk acute myeloid leukemia (AML). This is largely due to the ability of allogeneic immune system to eradicate leukemic stem cells (LSC). However, the fact that some patients still relapse after allo-HCT, suggests that strategies to increase LSC targeting by donor T cells are needed. For this purpose, we exploited the unique ability of myeloid blasts to differentiate into leukemic dendritic cells (LDC). We observed that a short (48h) exposure to calcium ionophore A23187 and IL-4 is able to induce LDC differentiation in 14/16 (86%) of AML that we studied, both de novo and secondary. Importantly, despite phenotypic and functional changes indicative of differentiation into DC-like cells, the process was accompanied by the maintenance of disease markers such as CD34 and CD117. Moreover, LDC maintained the expression of the oncogenic protein WT1, which is a putative LSC antigen. Thanks to these favourable characteristics, LDC proved to be superior to the original blasts in expanding leukemia-reactive T lymphocytes both in the autologous and allogeneic HCT setting (on average, 5-fold expansion of blasts-stimulated T cells vs 95-fold expansion of LDC-stimulated T cells, SEM=2,7 and 67,7 respectively, p=0,01). We observed that the level of T-cell expansion directly correlate with the percentage of LDC obtained upon treatment with A23187 and IL-4. Most importantly, LDC proved to be more potent than blasts in expanding central memory T lymphocytes (TCM), which are known to confer superior anti-tumor immunity (on average, 29% of TCM upon stimulation with blasts vs 53% TCM upon stimulation with LDC, SEM=7,2 and 5,7 respectively, p=0,01). LDC-expanded T lymphocytes were able to efficiently recognize and kill leukemic blasts in vitro (on average, 953 specific spots of IFN-g/50'000 effectors at E:T ratio of 10:1 -SEM=120- and 29% of specific killing at E:T ratio of 50:1 -SEM=7,4-). Importantly, analysis of different HLA-settings and different targets of patient origin, suggests that LDC can expand T lymphocytes with specificities against multiple antigens expressed by the original leukemia. In particular, we observed the expansion of WT-1 specific T cells upon LDC stimulation. Finally, when infused in NOD/Scid mice transplanted with the original leukaemia, LDC-stimulated T lymphocytes were able to induce long-term complete remissions (>16 weeks) in all mice analyzed, suggesting that this approach may be active against leukemic stem cells. These results show for the first time that LDC-stimulated human T cells could exert a strong GvL activity in vivo. Disclosures: Bordignon: Molmed Spa: Employment.

scholarly journals Authentic Patient-Derived Hepatitis C Virus Infects and Productively Replicates in Primary CD4+and CD8+T LymphocytesIn Vitro

2017 ◽  
Vol 92 (3) ◽  
Author(s):  
Georgia Skardasi ◽  
Annie Y. Chen ◽  
Tomasz I. Michalak
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Lymphocytes ◽  
Immune Cells ◽  
Immune Cell ◽  
Cell Types ◽  
Hcv Rna ◽  
Biophysical Properties

ABSTRACTAccumulated evidence indicates that immune cells can support the replication of hepatitis C virus (HCV) in infected patients and in culture. However, there is a scarcity of data on the degree to which individual immune cell types support HCV propagation and on characteristics of virus assembly. We investigated the ability of authentic, patient-derived HCV to infectin vitrotwo closely related but functionally distinct immune cell types, CD4+and CD8+T lymphocytes, and assessed the properties of the virus produced by these cells. The HCV replication system in intermittently mitogen-stimulated T cells was adapted to infect primary human CD4+or CD8+T lymphocytes. HCV replicated in both cell types although at significantly higher levels in CD4+than in CD8+T cells. Thus, the HCV RNA replicative (negative) strand was detected in CD4+and CD8+cells at estimated mean levels ± standard errors of the means of 6.7 × 102± 3.8 × 102and 1.2 × 102± 0.8 × 102copies/μg RNA, respectively (P< 0.0001). Intracellular HCV NS5a and/or core proteins were identified in 0.9% of CD4+and in 1.2% of CD8+T cells. Double staining for NS5a and T cell type-specific markers confirmed that transcriptionally competent virus replicated in both cell types. Furthermore, an HCV-specific protease inhibitor, telaprevir, inhibited infection in both CD4+and CD8+cells. The emergence of unique HCV variants and the release of HCV RNA-reactive particles with biophysical properties different from those of virions in plasma inocula suggested that distinct viral particles were assembled, and therefore, they may contribute to the pool of circulating virus in infected patients.IMPORTANCEAlthough the liver is the main site of HCV replication, infection of the immune system is an intrinsic characteristic of this virus independent of whether infection is symptomatic or clinically silent. Many fundamental aspects of HCV lymphotropism remain uncertain, including the degree to which different immune cells support infection and contribute to virus diversity. We show that authentic, patient-derived HCV productively replicatesin vitroin two closely related but functionally distinct types of T lymphocytes, CD4+and CD8+cells. The display of viral proteins and unique variants, the production of virions with biophysical properties distinct from those in plasma serving as inocula, and inhibition of replication by an antiviral agent led us to ascertain that both T cell subtypes supported virus propagation. Infection of CD4+and CD8+T cells, which are central to adaptive antiviral immune responses, can directly affect HCV clearance, favor virus persistence, and decisively influence the development and progression of hepatitis C.

scholarly journals Human Cytomegalovirus (HCMV)-Specific CD4+ T Cells Are Polyfunctional and Can Respond to HCMV-Infected Dendritic Cells In Vitro

2017 ◽  
Vol 91 (6) ◽  
Author(s):  
Sarah E. Jackson ◽  
George X. Sedikides ◽  
Gavin M. Mason ◽  
Georgina Okecha ◽  
Mark R. Wills
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Human Cytomegalovirus ◽  
Immune Cells ◽  
Cell Response ◽  
T Cell Response ◽  
Cell Responses ◽  
Infected Cells

ABSTRACT Human cytomegalovirus (HCMV) infection and periodic reactivation are generally well controlled by the HCMV-specific T cell response in healthy people. While the CD8+ T cell response to HCMV has been extensively studied, the HCMV-specific CD4+ T cell effector response is not as well understood, especially in the context of direct interactions with HCMV-infected cells. We screened the gamma interferon (IFN-γ) and interleukin-10 (IL-10) responses to 6 HCMV peptide pools (pp65, pp71, IE1, IE2, gB, and US3, selected because they were the peptides most frequently responded to in our previous studies) in 84 donors aged 23 to 74 years. The HCMV-specific CD4+ T cell response to pp65, IE1, IE2, and gB was predominantly Th1 biased, with neither the loss nor the accumulation of these responses occurring with increasing age. A larger proportion of donors produced an IL-10 response to pp71 and US3, but the IFN-γ response was still dominant. CD4+ T cells specific to the HCMV proteins studied were predominantly effector memory cells and produced both cytotoxic (CD107a expression) and cytokine (macrophage inflammatory protein 1β secretion) effector responses. Importantly, when we measured the CD4+ T cell response to cytomegalovirus (CMV)-infected dendritic cells in vitro, we observed that the CD4+ T cells produced a range of cytotoxic and secretory effector functions, despite the presence of CMV-encoded immune evasion molecules. CD4+ T cell responses to HCMV-infected dendritic cells were sufficient to control the dissemination of virus in an in vitro assay. Together, the results show that HCMV-specific CD4+ T cell responses, even those from elderly individuals, are highly functional and are directly antiviral. IMPORTANCE Human cytomegalovirus (HCMV) infection is carried for a lifetime and in healthy people is kept under control by the immune system. HCMV has evolved many mechanisms to evade the immune response, possibly explaining why the virus is never eliminated during the host's lifetime. The dysfunction of immune cells associated with the long-term carriage of HCMV has been linked with poor responses to new pathogens and vaccines when people are older. In this study, we investigated the response of a subset of immune cells (CD4+ T cells) to HCMV proteins in healthy donors of all ages, and we demonstrate that the functionality of CD4+ T cells is maintained. We also show that CD4+ T cells produce effector functions in response to HCMV-infected cells and can prevent virus spread. Our work demonstrates that these HCMV-specific immune cells retain many important functions and help to prevent deleterious HCMV disease in healthy older people.

scholarly journals 884 Engineered toxin body mediated depletion of TIGIT expressing immune cells for cancer immunotherapy

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A926-A926
Author(s):  
Elizabeth Saputra ◽  
Garrett Cornelison ◽  
Jennifer Mitchell ◽  
Karia Williams ◽  
Andrea Mendiola ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Cells ◽  
Immune Cell ◽  
Single Agent ◽  
Antibody Fragment ◽  
Cell Surface Receptor ◽  
Mouse Tumor ◽  
List Type ◽  
Proof Of Concept

BackgroundTIGIT (T cell immunoreceptor with Ig and ITIM domains) is an exciting novel target for immuno-oncology which functions as an immune checkpoint on multiple immune cell types including memory CD8+, CD4+ Treg, and memory CD4+ cells. TIGIT upregulation on tumor infiltrating lymphocytes (TILs) has been observed in multiple cancer types and contributes to an immunosuppressive tumor microenvironment (TME). Interestingly, TIGIT is commonly co-expressed with PD-1 on Tregs in the TME, tumor antigen specific CD8+ T cells and CD8+ TILs, leading to weakened anti-tumor immune responses.1–2 To date, TIGIT inhibiting monoclonal antibodies (mAb) have shown little activity as a monotherapy in clinical and preclinical studies. 3–4 Therefore, current clinical trials are now focused on combining TIGIT mAbs with known commercial PD-1 or PD-L1 mAbs. A TIGIT-specific engineered toxin body (ETB) represents a wholly new approach to targeting TIGIT expressing cells including those co-expressing TIGIT and PD-1.MethodsETBs targeting TIGIT were designed to deplete TIGIT-expressing TILs, including Tregs, directly in the TME. ETBs are proteins that consist of an antibody fragment genetically fused to a proprietary de-immunized (DI) form of the Shiga-like toxin A subunit (SLTA). These proteins are specific for a cell surface receptor, and function through triggering rapid internalization upon binding, followed by an enzymatic and irreversible termination of ribosomal protein synthesis resulting in cellular apoptosis. Here we provide proof of concept for ETBs as a novel modality for the depletion of TIGIT-expressing immune cells.ResultsTIGIT-targeting ETBs exhibit potent in vitro cytotoxicity of TIGIT over-expressing cell lines (IC50<1nM). These ETBs also lead to apoptotic depletion of ex vivo TIGIT-expressing regulatory T cells (Tregs) from healthy donors. In mixed culture assays, TIGIT ETBs increase the proliferation of TIGIT negative T cells by depleting TIGIT-expressing T cells.ConclusionsStudies to assess pharmacodynamics and efficacy of TIGIT targeting ETBs using a double knock-in (TIGIT and PD-1) mouse tumor model are ongoing, but these early proof of concept in vitro data support the hypothesis that ETBs can deplete TIGIT positive immune cell populations including those co-expressing PD-1. It is possible that targeted TIGIT inhibition through ETB-induced cell death could tip the balance towards tumor regression by eliminating this novel checkpoint (and TIGIT/PD-1 co-expression) at the level of the TME.ReferencesJinhua X, Ji W, Shouliang C, Liangfeng Z. Expression of immune checkpoints in T cells of esophageal cancer patients. Oncotarget 2016;7(39):1–10.Blessin NC, Simon R, Kluth M, Fischer K, et al. Patterns of TIGIT expression in lymphatic tissue, inflammation and cancer. Dis Markers 2019;2019:1–13.Johnston RJ, Comps-Agrar L, Hackney J, Yu X, et al. The immunoreceptor TIGIT regulates anti-tumor and antiviral CD8(+) T effector function. Cancer Cell 2014;26(6):923–927.Bendell JC, Bedrad P, Bang Y-J, LoRusso P, et al. Phase Ia/Ib dose-escalation study of the anti-TIGIT antibody Tiragolumab as a single agent and in combination with atezolizumab in patients with advanced solid tumors. Proceedings: AACR Annual Meeting 2020; April 27–28, 2020 and June 22–24, 2020; Philadelphia, PA.

scholarly journals Pre-Clinical Development of Gene Modification of Hematopoietic Stem Cells with Chimeric Antigen Receptors for Cancer Immunotherapy

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4430-4430
Author(s):  
Laurel Christine Truscott ◽  
Sarah Larson ◽  
Amie Patel ◽  
Roy L. Kao ◽  
Satiro N. De Oliveira
Keyword(s):  
Stem Cells ◽  
Clinical Trials ◽  
T Cells ◽  
Immune Cells ◽  
Suicide Gene ◽  
Antigen Specificity ◽  
Hematopoietic Stem ◽  
Cancer Activity

Abstract Background: Patients with refractory or recurrent B-lineage hematological malignancies have less than 50% of chance of cure, despite intensive therapy. Innovative approaches are needed to decrease their morbidity and mortality. Chimeric Antigen Receptors (CAR) successfully engineer antigen specificity in immune cells, with clinical trials currently being conducted using ex vivo expanded gene-modified mature T cells. Results from preclinical studies and clinical trials show that effector cells usually have transient in vivo persistence that could significantly limit clinical efficacy and allow tumor recurrence. Building upon the standard of care and seeking an approach that could foster persistence of the CAR-modified cells, we have published studies using anti-CD19 CAR-modified human hematopoietic stem cells (HSC) engrafted in NSG immunodeficient mice. We hypothesize that modification of HSC with CD19-specific CAR will generate persistent multi-lineage anti-tumor activity for immunotherapy of CD19+ hematological malignancies. To increase the safety of the modification of HSC, a suicide gene can be inserted into the vector to eradicate the modified cells in the setting of toxicity. Thorough evaluation of this approach in relevant study models is required for advancement to clinical trials. Significance: This approach is untested in clinical translation to this date, and implies harnessing a patient's own HSC to create a whole self-renewing immune system directed to destroy cancer, a concept that can be applied to different cancers just by adjusting the target specificity. The prospect of modifying autologous cells to enhance graft-versus-cancer activity bears the possibility of decreased morbidity and mortality, being desirable for specifically vulnerable populations, as children and elderly patients, and offering alternative therapy for those without cell sources available for allogeneic HSC transplantation, benefiting patients from ethnic minorities. This approach can be easily adopted in the clinical setting for patients planned to receive autologous HSC transplant as their standard therapy, enhancing graft-versus-cancer activity with anti-CD19 specificity. Methods: High-titer third-generation lentiviral constructs were produced carrying second-generation CD19-specific CAR co-stimulated by CD28. These vectors also co-delivered HSV-sr39TK to provide a suicide gene to allow ablation of gene-modified cells if necessary. Human HSC isolated from umbilical cord blood and G-CSF-mobilized apheresed peripheral blood stem cells (PBSC) were transduced with such lentiviral vectors and injected into NSG pups after irradiation for in vivo evaluation of engraftment, function and suicide gene activation. Results: We have consistently achieved engraftment of human cells in about 95% of study mice, with engraftment of CAR+ cells in about 80% of the animals. Human HSC were successfully transduced with lentiviral vectors carrying anti-CD19 CAR with no impairment of differentiation or proliferation in vitro and in vivo. Immune cells differentiated in vivo from CAR+ HSC had antigen-specific cytotoxicity directed by CAR. CAR+ human cells were detected in BM, spleen, blood and thymus of injected mice. CAR+ T cells were stably detected in the blood of engrafted mice up to 40 weeks post-injection, demonstrating lymphopoiesis of CAR+ T cells successfully escaping thymic deletion and persisting throughout murine lifetime. As a surrogate of the antigen specificity and efficacy, CD19+ cells were significantly decreased in all mice engrafted with anti-CD19 CAR demonstrating that CAR+ immune cells were not inactivated or developed tolerance. Mice humanized with at least 4% of CAR+ cells in blood had significant protection against challenge with CD19+ tumor cell line, with inhibition or elimination of tumor development and consequent survival advantage. Activation of HSV-sr39TK suicide gene by ganciclovir treatment successfully led to ablation of gene-modified cells in vitro and in vivo. Conclusions: Our results demonstrate feasibility of CAR modification of human HSC for cancer immunotherapy. It could be easily employed in the context of HSC transplantation to augment the anti-cancer activity, with CAR-expressing myeloid and NK cells to ensure tumor-specific immunity until de novo production of T cells from CAR-modified HSC. Disclosures Larson: BMS: Consultancy.

scholarly journals Five Genes as Diagnostic Markers of Ischemic Stroke and Their Correlation with Immune Infiltration

2021 ◽  
Author(s):  
Meng Wang ◽  
Ruijie Zhang ◽  
Qiongfeng Guan ◽  
Yindan Yao ◽  
Liyuan Han
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Ischemic Stroke ◽  
Immune Cells ◽  
Immune Cell ◽  
Diagnostic Markers ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Γδt Cells ◽  
Negatively Associated

Abstract Background: This study aimed to identify potential diagnostic markers of ischemic stroke (IS) and discuss the function of immune cell infiltration during the pathological process. Methods: We used IS datasets from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified, and functional correlation analysis was performed. We then screened and verified the diagnostic markers of IS. We evaluated the infiltration of immune cells in infarcts using CIBERSORT and analyzed the correlation between diagnostic markers and infiltrating immune cells. Results: A total of 366 DEGs were screened in this study. Genes encoding CTSG, F13A1, PABPC1, ECHDC2, BIRC2 and infiltrating monocytes, M0 macrophages, activated dendritic cells, and neutrophils (area under the curve [AUC] = 0.945) were identified as diagnostic markers of IS. Immune cell infiltration analysis suggested that memory B cells, regulatory T cells, M0 macrophages, CD8 + T cells, γδT cells, activated natural killer cells, monocytes, activated mast cells, and neutrophils were involved in the IS process. Analysis of correlations between expressed genes and infiltrating immune cells found that CTSG was positively associated with M0 macrophages, F13A1 was positively associated with monocytes, PABPC1 was positively associated with activated dendritic cells, eosinophils were negatively associated with neutrophils, ECHDC2 was negatively associated with monocytes, and BIRC2 was positively associated with eosinophils. Conclusion: five genes and four types of immune cells were identified as diagnostic markers of IS, and immune cell infiltration may play an important role in the progression of IS.

scholarly journals Molecular profiles and immunomodulatory activities of glioblastoma-derived exosomes

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Juliana Hofstatter Azambuja ◽  
Nils Ludwig ◽  
Saigopalakrishna Yerneni ◽  
Aparna Rao ◽  
Elizandra Braganhol ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
Cell Activation ◽  
Immune Cell ◽  
Size Exclusion ◽  
Cell Functions

Abstract Background Glioblastoma is one of the most immunosuppressive human tumors. Emerging data suggest that glioblastoma-derived exosomes (GBex) reprogram the tumor microenvironment into a tumor-promoting milieu by mechanisms that not yet understood. Methods Exosomes were isolated from supernatants of glioblastoma cell lines by size exclusion chromatography. The GBex endosomal origin, size, protein cargos, and ex vivo effects on immune cell functions were determined. GBex were injected intravenously into mice to evaluate their ability to in vivo modulate normal immune cell subsets. Results GBex carried immunosuppressive proteins, including FasL, TRAIL, CTLA-4, CD39, and CD73, but contained few immunostimulatory proteins. GBex co-incubated with primary human immune cells induced simultaneous activation of multiple molecular pathways. In CD8+ T cells, GBex suppressed TNF-α and INF-γ release and mediated apoptosis. GBex suppressed natural killer (NK) and CD4+ T-cell activation. GBex activated the NF-κB pathway in macrophages and promoted their differentiation into M2 cells. Inhibition of the NF-κB pathway in macrophages reversed the GBex-mediated effects. GBex-driven reprogramming of macrophages involved the release of soluble factors that promoted tumor proliferation in vitro. In mice injected with GBex, the frequency of splenic CD8+ T cells, NK cells, and M1-like macrophages was reduced, while that of naïve and M2-like macrophages increased (P &lt; .05). Conclusions GBex reprogrammed functions of all types of immune cells in vitro and altered their frequency in vivo. By creating and sustaining a highly immunosuppressive environment, GBex play a key role in promoting tumor progression.

scholarly journals When CAR Meets Stem Cells

2019 ◽  
Vol 20 (8) ◽  
pp. 1825 ◽  
Author(s):  
Jung Min Lee
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Stem Cell ◽  
Cell Therapy ◽  
Immune Cells ◽  
Pluripotent Stem Cells ◽  
Pluripotent Stem Cell ◽  
Immune Cell ◽  
Embryonic Stem ◽  
Lymphoid Cells

The generation of immune cells from human pluripotent stem cells (embryonic stem cells and induced pluripotent stem cells) has been of keen interest to regenerative medicine. Pluripotent stem cell-derived immune cells such as natural killer cells, macrophages, and lymphoid cells, especially T cells, can be used in immune cell therapy to treat incurable cancers. Moreover, since the advent of chimeric antigen receptor (CAR) technology, the success of CAR-T cells in the clinic has galvanized new efforts to harness the power of CAR technology to generate CAR-engineered immune cells from pluripotent stem cells. This review provides a summary of pluripotent stem cell-derived immune cells and CAR technology, together with perspectives on combining pluripotent stem-cell derived immune cells and CAR engineering to pave a new way for developing next generation immune cell therapy.

scholarly journals Extracellular Matrix Mechanical Properties and Regulation of the Intestinal Stem Cells: When Mechanics Control Fate

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2629
Author(s):  
Lauriane Onfroy-Roy ◽  
Dimitri Hamel ◽  
Julie Foncy ◽  
Laurent Malaquin ◽  
Audrey Ferrand
Keyword(s):  
Stem Cells ◽  
Extracellular Matrix ◽  
Intestinal Barrier ◽  
Intestinal Stem Cells ◽  
Cellular Events ◽  
Proliferation And Differentiation ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Intestinal Barrier Integrity

Intestinal stem cells (ISC) are crucial players in colon epithelium physiology. The accurate control of their auto-renewal, proliferation and differentiation capacities provides a constant flow of regeneration, maintaining the epithelial intestinal barrier integrity. Under stress conditions, colon epithelium homeostasis in disrupted, evolving towards pathologies such as inflammatory bowel diseases or colorectal cancer. A specific environment, namely the ISC niche constituted by the surrounding mesenchymal stem cells, the factors they secrete and the extracellular matrix (ECM), tightly controls ISC homeostasis. Colon ECM exerts physical constraint on the enclosed stem cells through peculiar topography, stiffness and deformability. However, little is known on the molecular and cellular events involved in ECM regulation of the ISC phenotype and fate. To address this question, combining accurately reproduced colon ECM mechanical parameters to primary ISC cultures such as organoids is an appropriated approach. Here, we review colon ECM physical properties at physiological and pathological states and their bioengineered in vitro reproduction applications to ISC studies.

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