| 1. |
- Ahlmanner, Filip, et al.
(författare)
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CD39+ regulatory T cells accumulate in colon adenocarcinomas and display markers of increased suppressive function
- 2018
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 9:97, s. 36993-37007
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Tidskriftsartikel (refereegranskat)abstract
- Increasing knowledge of the function and regulation of tumor-infiltrating lymphocytes has led to new insights in cancer immunotherapy. Regulatory T cells (Treg) accumulate in colon tumors, and we recently showed that CD39+ Treg from cancer patients inhibit transendothelial migration of conventional T cells. CD39 mediates the hydrolysis of ATP to immunosuppressive adenosine and adds to the immunosuppressive effects of Treg. Here, we further investigated the regulatory features of intratumoral CD39+ Treg in colon cancer. Using flow cytometry analyses of cells from 46 colon cancer patients, we confirm the accumulation of CD39+ Treg in the tumor tissue compared to unaffected colon tissue, and also show that tumor-infiltrating Treg express more CD39 and Foxp3 on a per cell basis. Furthermore, CD39+ Treg in tumors express markers indicating increased turnover and suppressive ability. In particular, tumor-infiltrating CD39+ Treg have high expression of surface molecules related to immunosuppression, such as ICOS, PD-L1 and CTLA-4. Functional suppression assays also indicate potent suppressive capacity of CD39+ Treg on proliferation and IFN-γ secretion by conventional T cells. In conclusion, our results identify tumor-infiltrating CD39+ Treg as a numerous and potentially important immunosuppressive subset, and suggest that immunotherapy aimed at reducing the activity of CD39+ Treg may be particularly useful in the setting of colon cancer. © 2018 Ahlmanner et al.
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| 2. |
- 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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| 3. |
- Alfredsson, Johannes, et al.
(författare)
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Isobaric labeling-based quantitative proteomics of FACS-purified immune cells and epithelial cells from the intestine of Crohn's disease patients reveals proteome changes of potential importance in disease pathogenesis.
- 2023
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Ingår i: Proteomics. - : Wiley. - 1615-9861 .- 1615-9853. ; 23:5
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Tidskriftsartikel (refereegranskat)abstract
- Crohn's disease (CD) is a chronic condition characterized by recurrent flares of inflammation in the gastrointestinal tract. Disease etiology is poorly understood and is characterized by dysregulated immune activation that progressively destroys intestinal tissue. Key cellular compartments in disease pathogenesis are the intestinal epithelial layer and its underlying lamina propria. While the epithelium contains predominantly epithelial cells, the lamina propria is enriched in immune cells. Deciphering proteome changes in different cell populations is important to understand CD pathogenesis. Here, using isobaric labeling-based quantitative proteomics, we perform an exploratory study to analyze in-depth proteome changes in epithelial cells, immune cells and stromal cells in CD patients compared to controls using cells purified by FACS. Our study revealed increased proteins associated with neutrophil degranulation and mitochondrial metabolism in immune cells of CD intestinal mucosa. We also found upregulation of proteins involved in glycosylation and secretory pathways in epithelial cells of CD patients, while proteins involved in mitochondrial metabolism were reduced. The distinct alterations in protein levels in immune- versus epithelial cells underscores the utility of proteome analysis of defined cell types. Moreover, our workflow allowing concomitant assessment of cell-type specific changes on an individual basis enables deeper insight into disease pathogenesis.
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| 4. |
- 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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| 5. |
- Bexe-Lindskog, Elinor, et al.
(författare)
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A population-based cohort study on adherence to practice guidelines for adjuvant chemotherapy in colorectal cancer
- 2014
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 14, s. 948-
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Tidskriftsartikel (refereegranskat)abstract
- Background: The value of adjuvant chemotherapy in colorectal cancer is well studied, and guidelines have been established. Little is known about how treatment guidelines are implemented in the everyday clinical setting. Methods: This national population-based study on nearly 34,000 patients with colorectal cancer evaluates the adherence to present clinical guidelines for adjuvant chemotherapy. Virtually all patients with colorectal cancer in Sweden during the years 2007-2012 and data from the Swedish Colorectal Cancer Registry were included. Results: In colon cancer stage III, adherence to national guidelines was associated with lower age, presence of multidisciplinary team (MDT) conference, low co-morbidity, and worse N stage. The MDT forum also affected whether or not high-risk stage II colon cancer patients were considered for adjuvant chemotherapy. Rectal cancer patients both in stage II and III were considered for adjuvant chemotherapy less often than colon cancer patients, but the same factors influenced the decision. Adjuvant chemotherapy was started later than eight weeks after surgery in 30% of colon cancer patients and in 38% of rectal cancer patients. Conclusions: In Sweden, the adherence to national guidelines for adjuvant chemotherapy in colon cancer stage III is acceptable in younger and healthier patients. MDT conferences are of major importance and affect whether patients are recommended for adjuvant chemotherapy. Special consideration needs to be given to certain subgroups of patients, particularly older patients and patients with poorly differentiated tumors. There is a need to shorten the waiting time until start of chemotherapy.
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| 6. |
- Bexe-Lindskog, Elinor
(författare)
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Experimental and population-based studies on colorectal cancer - Thymidine phosphorylase as a potential biomarker
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Colorectal cancer (CRC) is one of the most common malignancies, and the only reliable treatment option for cure is surgery. Method: Quantitative real-time polymerase chain reaction was used to analyze the gene expression of the enzyme thymidine phosphorylase (TP), which was related to prognostic factors (paper I, n=254), evaluated as a predictive factor (paper III, n=125), and assessed by change of treatment (paper II, n=28). Data from the Swedish Colorectal Cancer Registry were retrieved and analyzed in order to assess adherence to present clinical guidelines (n=34,000). Results: In stage III CRC, TP analyzed in tumor tissue correlated with lymph node staging, with higher expression levels relating to a greater number of positive nodes and a worse N-stage. Higher TP expression was also associated with a worse histological tumor grade. Rectal cancer exhibited significantly higher TP expression in mucosa and tumor tissue compared to colon cancer. There was a significant increase of TP gene expression when comparing rectal cancer biopsies before and after radiotherapy. In addition, a decrease in TP levels was noted after chemotherapy. In patients with metastatic CRC, time to progression was significantly longer in patients with high TP expression, but there was no correlation to tumor response rate or palliative survival. The factors associated with adherence to guideline treatment in colon cancer stage III patients were lower age, less comorbidity, worse N-stage, and presence of a multidisciplinary team conference. One-third of the patients started their adjuvant chemotherapy more than eight weeks after surgery. Conclusion: TP may be useful in prognostic and predictive situations. TP is affected by radiotherapy, which might be used in clinical settings. However, there are conflicting results, and TP and the methods of analyzing TP need to be evaluated further in larger studies. The adherence to guideline treatment in colon cancer stage III is acceptable in younger and healthier patients. In addition, there is scope for shortening the waiting time until the start of chemotherapy.
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| 7. |
- Bexe-Lindskog, Elinor, et al.
(författare)
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Thymidine phosphorylase expression is associated with time to progression in patients with metastatic colorectal cancer.
- 2014
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Ingår i: BMC clinical pathology. - : Springer Science and Business Media LLC. - 1472-6890. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- 5-Fluorouracil (5-FU) is the cornerstone of chemotherapeutic treatment for patients with colorectal cancer. The enzyme thymidine phosphorylase (TP) catalyzes the conversion of 5-FU to its active metabolite, 5-fluoro-2'-deoxyuridine. TP is expressed in tumour epithelial cells and stromal cells, particularly in tumour-associated macrophages. These macrophages may affect sensitivity to chemotherapy. Previously, we identified TP as a predictive factor in microdissected tumour samples of patients with advanced colorectal cancer. In the present study, we analysed TP expression in tissues and associated stromal cells from patients with advanced colorectal cancer and associated TP levels to tumour response and time-to-event variables during first-line chemotherapy treatment. We also investigated the association between serum TP levels at the time of surgery and gene expression in primary tumour tissues.
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| 8. |
- Bexe-Lindskog, Elinor, et al.
(författare)
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Thymidine Phosphorylase Gene Expression in Stage III Colorectal Cancer.
- 2012
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Ingår i: Clinical Medicine Insights. Oncology. - 1179-5549. ; 6, s. 347-53
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Tidskriftsartikel (refereegranskat)abstract
- The thymidine phosphorylase (TP) enzyme has several tumor-promoting functions. The aim of this study was to explore TP gene expression in relation to clinical and histopathological data obtained from patients with stage III colorectal cancer.
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| 9. |
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| 10. |
- Caër, Charles, et al.
(författare)
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TREM-1+ Macrophages Define a Pathogenic Cell Subset in the Intestine of Crohn's Disease Patients
- 2021
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Ingår i: Journal of Crohn's & colitis. - : Oxford University Press (OUP). - 1876-4479 .- 1873-9946. ; 15:8, s. 1346-1361
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: Uncontrolled activation of intestinal mononuclear phagocytes [MNPs] drives chronic inflammation in inflammatory bowel disease [IBD]. Triggering receptor expressed on myeloid cells 1 [TREM-1] has been implicated in the pathogenesis of IBD. However, the role of TREM-1+ cell subsets in driving IBD pathology and the link with clinical parameters are not understood. We investigated TREM-1 expression in human intestinal MNP subsets and examined blocking TREM-1 as a potential IBD therapy. METHODS: TREM-1 gene expression was analysed in intestinal mucosa, enriched epithelial and lamina propria [LP] layers, and purified cells from controls and IBD patients. TREM-1 protein on immune cells was assessed by flow cytometry and immunofluorescence microscopy. Blood monocyte activation was examined by large-scale gene expression using a TREM-1 agonist or LP conditioned media [LP-CM] from patients in the presence or absence of TREM-1 and tumour necrosis factor [TNF] antagonist antibodies. RESULTS: TREM-1 gene expression increases in intestinal mucosa from IBD patients and correlates with disease score. TREM-1+ cells, which are mainly immature macrophages and CD11b+ granulocytes, increase among LP cells from Crohn's disease patients and their frequency correlates with inflammatory molecules in LP-CM. LP-CM from Crohn's disease patients induces an inflammatory transcriptome in blood monocytes, including increased IL-6 expression, which is reduced by simultaneous blocking of TREM-1 and TNF. CONCLUSIONS: High intestinal TREM-1 expression, reflecting a high frequency of TREM-1+ immature macrophages and TREM-1+CD11b+ granulocytes, is linked to the deleterious inflammatory microenvironment in IBD patients. Therefore, blocking the TREM-1 pathway, especially simultaneously with anti-TNF therapy, has potential as a new IBD therapy.
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