| 1. |
- Akeus, Paulina, et al.
(författare)
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Regulatory T cells reduce endothelial neutral sphingomyelinase 2 to prevent T-cell migration into tumors
- 2021
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Ingår i: European Journal of Immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 51:9, s. 2317-2329
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Tidskriftsartikel (refereegranskat)abstract
- Endothelial cells are key regulators of transendothelial migration and their secretion of chemokines and expression of adhesion molecules facilitates lymphocyte entry into tissues. Previously, we demonstrated that Tregs can reduce transendothelial migration of T cells into tumors by decreasing endothelial CXCL10 secretion, but the mechanism by which this occurs is still not known. In this study, we aimed to define how Tregs decrease transendothelial migration into tumors. mRNA sequencing of intestinal tumor endothelial cells from Treg depleted mice identified neutral sphingomyelinase 2 (nSMase2) as a gene downregulated in the presence of Tregs. nSMase2 is expressed in human umbilical vein endothelial cells (HUVECs) and was decreased after coculture with Tregs. Furthermore, blocking of nSMase2 activity in vitro decreased VCAM1, CX3CL1, and CXCL10 expression in HUVECs, mirroring the same decrease found in Treg cocultures. In the APC(min/+) mouse model of intestinal cancer, nSMase2 is lower in tumor endothelial cells than in unaffected small intestine and chronic treatment with a nSMase2 inhibitor suppressed the increased migration that is otherwise seen in the absence of Tregs. We conclude that nSMase2 is an important mediator in endothelial cells supporting transendothelial migration, which may be targeted by Tregs to reduce T-cell migration into tumors.
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| 2. |
- Andric, Fanny, et al.
(författare)
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Immune Microenvironment in Sporadic Early-Onset versus Average-Onset Colorectal Cancer
- 2023
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 15:5
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Tidskriftsartikel (refereegranskat)abstract
- Simple Summary The incidence of non-hereditary cancer in the left colon and rectum is increasing in young patients worldwide for unknown reasons. To understand this phenomenon, the biology of early-onset colorectal cancer needs to be established. Here, we investigated the immune response to tumors by selecting a highly representative group of patients younger than 45 years matched to those aged 70-75 years, excluding hereditary cases. Both T-cell distribution in tumors and expression of 770 immune-related genes were overall similar between the groups. The findings suggest that the immune response in cancer of the left colon and rectum is not dependent on age and that early-onset colorectal cancer is likely not related to immune response deficiencies. The incidence of left-sided colon and rectal cancer in young people are increasing worldwide, but its causes are poorly understood. It is not clear if the tumor microenvironment is dependent on age of onset, and little is known about the composition of tumor-infiltrating T cells in early-onset colorectal cancer (EOCRC). To address this, we investigated T-cell subsets and performed gene expression immune profiling in sporadic EOCRC tumors and matched average-onset colorectal cancer (AOCRC) tumors. Left-sided colon and rectal tumors from 40 cases were analyzed; 20 EOCRC (<45 years) patients were matched 1:1 to AOCRC (70-75 years) patients by gender, tumor location, and stage. Cases with germline pathogenic variants, inflammatory bowel disease or neoadjuvant-treated tumors were excluded. For T cells in tumors and stroma, a multiplex immunofluorescence assay combined with digital image analysis and machine learning algorithms was used. Immunological mediators in the tumor microenvironment were assessed by NanoString gene expression profiling of mRNA. Immunofluorescence revealed no significant difference between EOCRC and AOCRC with regard to infiltration of total T cells, conventional CD4(+) and CD8(+) T cells, regulatory T cells, or gamma delta T cells. Most T cells were located in the stroma in both EOCRC and AOCRC. Immune profiling by gene expression revealed higher expression in AOCRC of the immunoregulatory cytokine IL-10, the inhibitory NK cell receptors KIR3DL3 and KLRB1 (CD161), and IFN-a7 (IFNA7). In contrast, the interferon-induced gene IFIT2 was more highly expressed in EOCRC. However, in a global analysis of 770 tumor immunity genes, no significant differences could be detected. T-cell infiltration and expression of inflammatory mediators are similar in EOCRC and AOCRC. This may indicate that the immune response to cancer in left colon and rectum is not related to age of onset and that EOCRC is likely not driven by immune response deficiency.
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| 3. |
- Kraft, Jamie D., et al.
(författare)
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Lipoxins modulate neutrophil oxidative burst, integrin expression and lymphatic transmigration differentially in human health and atherosclerosis
- 2022
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Ingår i: FASEB Journal. - Hoboken, NJ, United States : John Wiley & Sons. - 0892-6638 .- 1530-6860. ; 36:3
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Tidskriftsartikel (refereegranskat)abstract
- Dysregulated chronic inflammation plays a crucial role in the pathophysiology of atherosclerosis and may be a result of impaired resolution. Thus, restoring levels of specialized pro-resolving mediators (SPMs) to promote the resolution of inflammation has been proposed as a therapeutic strategy for patients with atherosclerosis, in addition to standard clinical care. Herein, we evaluated the effects of the SPM lipids, lipoxin A4 (LXA4) and lipoxin B4 (LXB4), on neutrophils isolated from patients with atherosclerosis compared with healthy controls. Patients displayed altered endogenous SPM production, and we demonstrated that lipoxin treatment in whole blood from atherosclerosis patients attenuates neutrophil oxidative burst, a key contributor to atherosclerotic development. We found the opposite effect in neutrophils from healthy controls, indicating a potential mechanism whereby lipoxins aid the endogenous neutrophil function in health but reduce its excessive activation in disease. We also demonstrated that lipoxins attenuated upregulation of the high-affinity conformation of the CD11b/CD18 integrin, which plays a central role in clot activation and atherosclerosis. Finally, LXB4 enhanced lymphatic transmigration of human neutrophils isolated from patients with atherosclerosis. This finding is noteworthy, as impaired lymphatic function is now recognized as an important contributor to atherosclerosis. Although both lipoxins modulated neutrophil function, LXB4 displayed more potent effects than LXA4 in humans. This study highlights the therapeutic potential of lipoxins in atherosclerotic disease and demonstrates that the effect of these SPMs may be specifically tailored to the need of the individual. © 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.
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| 4. |
- Kraft, Jamie D., et al.
(författare)
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Specialized Pro-Resolving Mediators and the Lymphatic System
- 2021
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067 .- 1661-6596. ; 22:5
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Tidskriftsartikel (refereegranskat)abstract
- Diminished lymphatic function and abnormal morphology are common in chronic inflammatory diseases. Recent studies are investigating whether it is possible to target chronic inflammation by promoting resolution of inflammation, in order to enhance lymphatic function and attenuate disease. Resolution of inflammation is an active process regulated by bioactive lipids known as specialized pro-resolving mediators (SPMs). SPMs can modulate leukocyte migration and function, alter cytokine/chemokine release, modify autophagy, among other immune-related activities. Here, we summarize the role of the lymphatics in resolution of inflammation and lymphatic impairment in chronic inflammatory diseases. Furthermore, we discuss the current literature describing the connection between SPMs and the lymphatics, and the possibility of targeting the lymphatics with innovative SPM therapy to promote resolution of inflammation and mitigate disease.
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| 5. |
- Liang, Frank, et al.
(författare)
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Antigen Presenting Cells from Tumor and Colon of Colorectal Cancer Patients Are Distinct in Activation and Functional Status, but Comparably Responsive to Activated T Cells.
- 2021
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:20
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Tidskriftsartikel (refereegranskat)abstract
- Although mouse models of CRC treatments have demonstrated robust immune activation, it remains unclear to what extent CRC patients' APCs and TILs interact to fuel or quench treatment-induced immune responses. Our ex vivo characterization of tumor and adjacent colon cell suspensions suggest that contrasting environments in these tissues promoted inversed expression of T cell co-stimulatory CD80, and co-inhibitory programmed death (PD)-ligand1 (PD-L1) on intratumoral vs. colonic APCs. While putative tumor-specific CD103+CD39+CD8+ TILs expressed lower CD69 (early activation marker) and higher PD-1 (extended activation/exhaustion marker) than colonic counterparts, the latter had instead higher CD69 and lower PD-1 levels. Functional comparisons showed that intratumoral APCs were inferior to colonic APCs regarding protein uptake and upregulation of CD80 and PD-L1 after protein degradation. Our attempt to model CRC treatment-induced T cell activation in vitro showed less interferon (IFN)-γ production by TILs than colonic T cells. In this model, we also measured APCs' CD80 and PD-L1 expression in response to activated co-residing T cells. These markers were comparable in the two tissues, despite higher IFN- γ exposure for colonic APCs. Thus, APCs within distinct intratumoral and colonic milieus showed different activation and functional status, but were similarly responsive to signals from induced T cell activation.
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| 6. |
- Rodin, William, 1994, et al.
(författare)
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Isolation and Characterization of MAIT Cells from Tumor Tissues
- 2020
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Ingår i: MAIT Cells. Methods and Protocols. Helen KaipeIsabelle Magalhaes (red.). - New York, NY : Springer. - 9781071602065 ; , s. 39-53
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Mucosal-associated invariant T (MAIT) cell infiltration has been demonstrated in colorectal and hepatocellular carcinoma, and their ability to produce Th1- and Th17-associated cytokines, as well as their cytotoxic function, suggests that MAIT cells may have important functions in both reducing and promoting protective tumor immunity. Here, we describe enzymatic methods to isolate intraepithelial and lamina propria lymphocyte single cell suspensions from colon tissue and tumors containing viable MAIT cells, which can be used for further purification, flow cytometry analysis, or culture.
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| 7. |
- Sotak, Matus, et al.
(författare)
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Lipoxins reduce obesity-induced adipose tissue inflammation in 3D-cultured human adipocytes and explant cultures
- 2022
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Ingår i: iScience. - : Elsevier BV. - 2589-0042. ; 25:7
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Tidskriftsartikel (refereegranskat)abstract
- Adipose tissue inflammation drives obesity-related cardiometabolic diseases. Enhancing endogenous resolution mechanisms through administration of lipoxin A4, a specialized pro-resolving lipid mediator, was shown to reduce adipose inflammation and subsequently protects againstobesity-inducedsystemic disease inmice. Here, we demonstrate that lipoxins reduce inflammation in 3D-cultured human adipocytes and adipose tissue explants from obese patients. Approximately 50% of patients responded particularlywell to lipoxins by reducing inflammatory cytokines and promoting an anti-inflammatory M2 macrophage phenotype. Responding patients were characterized by elevated systemic levels of C-reactive protein, which causes inflammation in cultured human adipocytes. Responders appeared more prone to producing anti-inflammatory oxylipins and displayed elevated prostaglandin D2 levels, which has been interlinked with transcription of lipoxin-generatingenzymes. Using explant cultures, this study provides the first proof-of-concept evidence supporting the therapeutic potential of lipoxins in reducing human adipose tissue inflammation. Our data further indicate that lipoxin treatment may require a tailored personalized-medicine approach.
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| 8. |
- Sundström, Patrik, et al.
(författare)
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Immune cell infiltrates in peritoneal metastases from colorectal cancer
- 2024
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Ingår i: FRONTIERS IN IMMUNOLOGY. - 1664-3224. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Background: The presence of peritoneal metastases (PMs) in patients with colorectal cancer (CRC) confers a poor prognosis and only a minority of patients will benefit from the available treatment options. In primary CRC tumors, it is well established that a high infiltration of CD8+ effector T cells correlates to a favorable patient outcome. In contrast, the immune response induced in PMs from CRC and how it relates to patient survival is still unknown. In this study, we characterized the immune infiltrates and the distribution of immune checkpoint receptors on T cells from PMs from CRC, in order to evaluate the potential benefit of checkpoint blockade immunotherapy for this patient group. Methods: Surgically resected PM tissue from CRC patients (n=22) and synchronous primary tumors (n=8) were processed fresh to single cell suspensions using enzymatic digestion. Surface markers and cytokine production were analyzed using flow cytometry. Results: T cells dominated the leukocyte infiltrate in the PM specimens analyzed, followed by monocytes and B cells. Comparing two different PMs from the same patient usually showed a similar distribution of immune cells in both samples. The T cell infiltrate was characterized by an activated phenotype and markers of exhaustion were enriched compared with matched circulating T cells, in particular the checkpoint receptors PD-1 and TIGIT. In functional assays most cytotoxic and helper T cells produced INF-g and TNF following polyclonal stimulation, while few produced IL-17, indicating a dominance of Th1-type responses in the microenvironment of PMs. Conclusion: Immune cells were present in all PMs from CRC examined. Although infiltrating T cells express markers of exhaustion, they produce Th1-type cytokines when stimulated. These results indicate the possibility to augment tumor-specific immune responses within PMs using checkpoint blockade inhibitors.
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| 9. |
- Sundström, Patrik, et al.
(författare)
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Immune checkpoint blockade improves the activation and function of circulating mucosal-associated invariant T (MAIT) cells in patients with non-small cell lung cancer
- 2024
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Ingår i: OncoImmunology. - 2162-4011 .- 2162-402X. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Mucosal-associated invariant T (MAIT) cells constitute one of the most numerous unconventional T cell subsets, and are characterized by rapid release of Th1- and Th17-associated cytokines and increased cytotoxic functions following activation. MAIT cells accumulate in tumor tissue but show an exhausted phenotype. Here, we investigated if immune checkpoint blockade (ICB) with antibodies to PD-1 or PD-L1 affects the function of circulating MAIT cells from non-small cell lung cancer patients. ICB increased the proliferation and co-expression of the activation markers HLA-DR and CD38 on MAIT cells in most patients after the first treatment cycle, irrespective of treatment outcome. Furthermore, production of cytokines, especially TNF and IL-2, also increased after treatment, as did MAIT cell polyfunctionality. These results indicate that MAIT cells respond to ICB, and that MAIT cell reinvigoration may contribute to tumor regression in patients undergoing immune checkpoint therapy.
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| 10. |
- Szeponik, Louis, et al.
(författare)
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Intratumoral regulatory T cells from colon cancer patients comprise several activated effector populations
- 2021
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Ingår i: Bmc Immunology. - : Springer Science and Business Media LLC. - 1471-2172. ; 22:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Intratumoral regulatory T cells (Treg) in colon cancer are a heterogeneous cell population, with potential impact on patient outcome. Generally, a high Treg infiltration has been correlated to a worse patient outcome, but it is still unclear how the composition of different Treg subsets affects patient relapse and survival. In this study, we used mass and flow cytometry to characterize Treg in colon tumors and corresponding unaffected tissue, followed by a correlation to clinical parameters and patient outcome. Results Using mass cytometry, we defined 13 clusters of intestinal Treg, three of which were enriched in the tumors. The two most enriched clusters were defined by their expression of the proliferation marker Ki67 and CD56, respectively. The Treg accumulating in the tumors expressed inducible T-cell co-stimulator (ICOS), OX-40, and CD39, indicating that they were effector Treg (eTreg). Intratumoral CD39(+) Treg also had a higher expression of Foxp3, suggesting a higher suppressive activity, and we subsequently used CD39 as a marker for eTreg. Our further studies showed that colon tumors can be divided into two tumor groups, based on the proportion of CD39(+) putative eTreg in the tumors. This property was independent of both tumor microsatellite status and tumor stage, which are important factors in predicting cancer disease progression. In a prospective study of forty-four colon cancer patients, we also showed that patients with a high CD39 expression on tumor-infiltrating Treg have a tendency towards a less favorable patient outcome in terms of cumulative cancer-specific survival. Conclusions This study uncovers novel subsets of tumor-infiltrating Treg in colon cancer, and suggests that CD39 may be a potential therapeutic target in patients with microsatellite stable colon tumors, which are usually refractory to checkpoint blockade therapy.
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