| 1. |
- Akeus, Paulina, et al.
(author)
-
Regulatory T cells control endothelial chemokine production and migration of T cells into intestinal tumors of APC(min/+) mice
- 2018
-
In: Cancer Immunology Immunotherapy. - : Springer Science and Business Media LLC. - 0340-7004 .- 1432-0851. ; 67:7, s. 1067-1077
-
Journal article (peer-reviewed)abstract
- Tumor-infiltrating lymphocytes are crucial for anti-tumor immunity. We have previously shown that regulatory T cells (Treg) are able to reduce T-cell transendothelial migration in vitro and accumulation of effector T cells in intestinal tumors in vivo. Treg depletion also resulted in increased levels of the chemokines CXCL9 and CXCL10 specifically in the tumors. In this study, we investigated the mechanisms for Treg mediated suppression of T-cell migration into intestinal tumors in the APC(min/+) mouse model. By breeding APC(min/+) mice with DEREG mice, which harbour a high affinity diphtheria toxin receptor under the control of the FOXP3 promoter, we were able to deplete Treg in tumor-bearing mice. Using adoptive transfer experiments, we could document a markedly increased migration of T cells specifically into Treg depleted tumors, and that Treg depletion results in increased production of the CXCR3 ligand CXCL10 from endothelial cells in the tumors. Furthermore, we were able to demonstrate that T cells use CXCR3 to migrate into intestinal tumors. In addition, human colon adenocarcinomas express high levels of mRNA CXCR3 ligands and tumor endothelial cells produce CXCL9 and CXCL10 ex vivo. In conclusion, this study demonstrates that Treg reduce endothelial CXCL10 production, inhibit T-cell migration into tumors and that CXCR3 mediated signalling is crucial for lymphocyte accumulation in intestinal tumors. Thus, immunotherapy aimed at Treg depletion may be effective by increasing not only T effector cell activity, but also their accumulation in tumors.
|
|
| 2. |
- Akeus, Paulina, et al.
(author)
-
Regulatory T cells reduce endothelial neutral sphingomyelinase 2 to prevent T-cell migration into tumors
- 2021
-
In: European Journal of Immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 51:9, s. 2317-2329
-
Journal article (peer-reviewed)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.
|
|
| 3. |
- Alsén, Samuel, et al.
(author)
-
Antigen-Presenting B Cells Program the Efferent Lymph T Helper Cell Response
- 2022
-
In: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 13
-
Journal article (peer-reviewed)abstract
- B cells interact with T follicular helper (Tfh) cells in germinal centers (GCs) to generate high-affinity antibodies. Much less is known about how cognate T-B-cell interactions influence Th cells that enter circulation and peripheral tissues. Therefore, we generated mice lacking MHC-II expressing B cells and, by thoracic duct cannulation, analyzed Th cells in the efferent lymph at defined intervals post-immunization. Focusing on gut-draining mesenteric lymph nodes (MLNs), we show that antigen-specific alpha(4)beta(+)(7) gut-homing effector Th cells enter the circulation prior to CXCR5(+)PD-1(+) Tfh-like cells. B cells appear to have no or limited impact on the early generation and egress of gut-homing Th cells but are critical for the subsequent appearance of Tfh-like cells that peak in the lymph before GCs have developed. At this stage, antigen-presenting B cells also reduce the proportion of alpha(4)beta(+)(7) Th cells in the MLN and efferent lymph. Furthermore, cognate B-cell interaction drives a broad transcriptional program in Th cells, including IL-4 that is confined to the Tfh cell lineage. The IL-4-producing Tfh-like cells originate from Bcl6(+) precursors in the LNs and have gut-homing capacity. Hence, B cells program the efferent lymph Th cell response within a limited window of time after antigenic challenge.
|
|
| 4. |
- Andric, Fanny, et al.
(author)
-
Immune Microenvironment in Sporadic Early-Onset versus Average-Onset Colorectal Cancer
- 2023
-
In: Cancers. - : MDPI AG. - 2072-6694. ; 15:5
-
Journal article (peer-reviewed)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.
|
|
| 5. |
- Caër, Charles, et al.
(author)
-
TREM-1+ Macrophages Define a Pathogenic Cell Subset in the Intestine of Crohn's Disease Patients
- 2021
-
In: Journal of Crohn's & colitis. - : Oxford University Press (OUP). - 1876-4479 .- 1873-9946. ; 15:8, s. 1346-1361
-
Journal article (peer-reviewed)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.
|
|
| 6. |
- Kaidi, Donia, et al.
(author)
-
Impact of thymidine phosphorylase and CD163 expression on prognosis in stage II colorectal cancer
- 2022
-
In: Clinical & Translational Oncology. - : Springer Science and Business Media LLC. - 1699-048X .- 1699-3055. ; 24:9, s. 1818-1827
-
Journal article (peer-reviewed)abstract
- Background Tumor-associated macrophages (TAM) are known to facilitate colorectal cancer (CRC) growth. High macrophage infiltration in thymidine phosphorylase (TYMP) expressing CRC may correspond to poor prognosis. The prognostic impact of the expression CD163, a receptor associated with TAM, and TYMP in stroma, respectively, tumor tissue is not yet established. The aim of this study was to identify the potential associations between TYMP and CD163 expression levels and relapse-free survival (RFS) of patients with stage II CRC, and if microdissection is of importance. Methods Stage II CRC patients, radically resected with relapse (n = 104), were matched to patients with a 5-year relapse-free follow-up (n = 206). Gene expression of TYMP and CD163 was analyzed in snap-frozen tumor tissues and in microdissected formalin-fixed tumor tissues separated into tumor epithelium and stroma. Results TYMP expression was high in poorly differentiated tumors, right-sided CRC, and tumors with high microsatellite instability CD163-expressing macrophages near tumor epithelial cells had high expression in poorly differentiated and T4 tumors. High TYMP expression in tumor epithelial cells was in the multivariate analyses associated with shorter relapse-free survival (hazard ratio 1.66; 95% confidence interval: 1.09-2.56; p < 0.05). Conclusions TYMP expression in tumor epithelial cells was associated with RFS and emphasizes the need for tissue microdissection. Additional studies are needed to establish whether TYMP and CD163 could add clinically relevant information to identify high-risk stage II patients that could benefit from adjuvant chemotherapy.
|
|
| 7. |
- Krishnaswamy, Jayendra Kumar, et al.
(author)
-
Migratory CD11b+ conventional dendritic cells induce T follicular helper cell-dependent antibody responses.
- 2017
-
In: Science immunology. - : American Association for the Advancement of Science (AAAS). - 2470-9468. ; 2:18
-
Journal article (peer-reviewed)abstract
- T follicular helper (Tfh) cells are a subset of CD4+ T cells that promote antibody production during vaccination. Conventional dendritic cells (cDCs) efficiently prime Tfh cells; however, conclusions regarding which cDC instructs Tfh cell differentiation have differed between recent studies. We found that these discrepancies might exist because of the unusual sites used for immunization in murine models, which differentially bias which DC subsets access antigen. We used intranasal immunization as a physiologically relevant route of exposure that delivers antigen to all tissue DC subsets. Using a combination of mice in which the function of individual DC subsets is impaired and different antigen formulations, we determined that CD11b+ migratory type 2 cDCs (cDC2s) are necessary and sufficient for Tfh induction. DC-specific deletion of the guanine nucleotide exchange factor DOCK8 resulted in an isolated loss of CD11b+ cDC2, but not CD103+ cDC1, migration to lung-draining lymph nodes. Impaired cDC2 migration or development in DC-specific Dock8 or Irf4 knockout mice, respectively, led to reduced Tfh cell priming, whereas loss of CD103+ cDC1s in Batf3-/- mice did not. Loss of cDC2-dependent Tfh cell priming impaired antibody-mediated protection from live influenza virus challenge. We show that migratory cDC2s uniquely carry antigen into the subanatomic regions of the lymph node where Tfh cell priming occurs-the T-B border. This work identifies the DC subset responsible for Tfh cell-dependent antibody responses, particularly when antigen dose is limiting or is encountered at a mucosal site, which could ultimately inform the formulation and delivery of vaccines.
|
|
| 8. |
- Liang, Frank, et al.
(author)
-
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
-
In: Cancers. - : MDPI AG. - 2072-6694. ; 13:20
-
Journal article (peer-reviewed)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.
|
|
| 9. |
- Rodin, William, 1994, et al.
(author)
-
Exhaustion in tumor-infiltrating Mucosal-Associated Invariant T (MAIT) cells from colon cancer patients
- 2021
-
In: Cancer Immunology Immunotherapy. - : Springer Science and Business Media LLC. - 0340-7004 .- 1432-0851. ; 70, s. 3461-3475
-
Journal article (peer-reviewed)abstract
- Mucosal-associated invariant T (MAIT) cells are unconventional T cells recognizing microbial metabolites, presented by the invariant MR1 protein. Upon activation, MAIT cells rapidly secrete cytokines and exert cytotoxic functions, and may thus be highly relevant also in tumor immunity. MAIT cells accumulate in colon tumors, but in contrast to other cytotoxic T cell subsets, their presence in tumors has been associated with worse patient outcome. Here we investigated if exhaustion may contribute to reduced anti-tumor immunity by MAIT cells. Freshly isolated lymphocytes from colon tumors, unaffected tissue and blood from the same patients were analyzed by flow cytometry to detect MAIT cells with effector functions that are relevant for tumor immunity, and their expression of inhibitory receptors and other exhaustion markers. Our studies show that MAIT cells with a PD-1(high)Tim-3(+)CD39(+) terminally exhausted phenotype and an increased proliferation accumulate in colon tumors. The exhausted MAIT cells have reduced polyfunctionality with regard to production of important anti-tumor effector molecules, and blocking antibodies to PD-1 partly improved activation of tumor-infiltrating MAIT cells in vitro. We conclude that the tumor microenvironment leads to exhaustion not only of conventional T cells, but also MAIT cells, and that checkpoint blockade therapy may be useful also to reinvigorate tumor-infiltrating MAIT cells.
|
|
| 10. |
- Sharba, Sinan, et al.
(author)
-
Interleukin 4 induces rapid mucin transport, increases mucus thickness and quality and decreases colitis and Citrobacter rodentium in contact with epithelial cells
- 2019
-
In: Virulence. - : Informa UK Limited. - 2150-5594 .- 2150-5608. ; 10:1, s. 97-117
-
Journal article (peer-reviewed)abstract
- Citrobacter rodentium infection is a murine model for pathogenic intestinal Escherichia coli infection. C. rodentium infection causes an initial decrease in mucus layer thickness, followed by an increase during clearance. We aimed to identify the cause of these changes and to utilize this naturally occurring mucus stimulus to decrease pathogen impact and inflammation. We identified that mucin production and speed of transport from Golgi to secretory vesicles at the apical surface increased concomitantly with increased mucus thickness. Of the cytokines differentially expressed during increased mucus thickness, IFN-gamma and TNF-alpha decreased the mucin production and transport speed, whereas IL-4, IL-13, C. rodentium and E. coli enhanced these aspects. IFN-gamma and TNF-alpha treatment in combination with C. rodentium and pathogenic E. coli infection negatively affected mucus parameters in vitro, which was relieved by IL-4 treatment. The effect of IL-4 was more pronounced than that of IL-13, and in wild type mice, only IL-4 was present. Increased expression of Il-4, Il-4-receptor alpha, Stat6 and Spdef during clearance indicate that this pathway contributes to the increase in mucin production. In vivo IL-4 administration initiated 10 days after infection increased mucus thickness and quality and decreased colitis and pathogen contact with the epithelium. Thus, during clearance of infection, the concomitant increase in IL-4 protects and maintains goblet cell function against the increasing levels of TNF-alpha and IFN-gamma. Furthermore, IL-4 affects intestinal mucus production, pathogen contact with the epithelium and colitis. IL-4 treatment may thus have therapeutic benefits for mucosal healing.
|
|
| 11. |
- Sundström, Patrik, et al.
(author)
-
Tumor-infiltrating mucosal-associated invariant T (MAIT) cells retain expression of cytotoxic effector molecules.
- 2019
-
In: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 10:29, s. 2810-2823
-
Journal article (peer-reviewed)abstract
- Mucosal-associated invariant T (MAIT) cells all express a semi-invariable T cell receptor recognizing microbial metabolites presented on the MHC class I-like molecule MR1. Upon activation, they rapidly secrete cytokines and increase their cytotoxic potential. We showed recently that MAIT cells with Th1 phenotype accumulate in human colon adenocarcinomas. Here, we investigated the cytotoxic potential of tumor-infiltrating MAIT cells in colon adenocarcinomas, and to what extent it may be affected by the tumor microenvironment. Activation of MAIT cells from tumors induced increased Granzyme B, and to a lesser extent, perforin expression. Degranulation was assessed by surface expression of CD107a, and was also seen in response to cognate antigen recognition. The cytotoxic potential of tumor-associated MAIT cells was very similar to that of MAIT cells from unaffected colon. MAIT cells were also identified by immunofluorescence in direct contact with tumor cells in sections from colon cancer specimens. To summarize, tumor-associated MAIT cells from colon tumors have strong cytotoxic potential and are not compromised in this regard compared to MAIT cells from the unaffected colon. We conclude that MAIT cells may contribute significantly to the protective immune response to tumors, both by secretion of Th1-associated cytokines and by direct killing of tumor cells.
|
|
| 12. |
- Szeponik, Louis, et al.
(author)
-
Intratumoral regulatory T cells from colon cancer patients comprise several activated effector populations
- 2021
-
In: Bmc Immunology. - : Springer Science and Business Media LLC. - 1471-2172. ; 22:1
-
Journal article (peer-reviewed)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.
|
|
| 13. |
- Szeponik, Louis, et al.
(author)
-
Regulatory T cells specifically suppress conventional CD8 alpha beta T cells in intestinal tumors of APC(Min/+) mice
- 2020
-
In: Cancer Immunology, Immunotherapy. - : Springer Science and Business Media LLC. - 0340-7004 .- 1432-0851. ; 69, s. 1279-1292
-
Journal article (peer-reviewed)abstract
- The presence of activated T cells in colorectal cancer tissues is a strong predictor of patient survival. Our previous studies have shown that regulatory T cells (Treg) are able to reduce T cell transendothelial migration in vitro and accumulation of effector T cells in intestinal tumors in vivo in the murine APC(Min/+) model for microsatellite stable intestinal tumors. In this study, we investigated the effect of Treg depletion on the density and effector functions of different TCR alpha beta(+) and TCR gamma delta(+) T cell populations in intestinal tumors. We used the APC(Min/+)\DEREG mouse model, which harbor a diphtheria toxin receptor under the control of the FOXP3 promoter, to deplete Treg in tumor bearing mice. We found that the density of conventional TCR alpha beta(+)CD8 alpha beta(+) T cells was significantly increased in Treg-depleted tumors in comparison with Treg-proficient tumors. Furthermore, TCR alpha beta(+)CD8 alpha beta(+) T cells showed increased proliferation and activation as well as increased Granzyme B and IFN-gamma production in Treg-depleted tumors. In sharp contrast, the densities and effector functions of TCR alpha beta(+)CD8 alpha alpha(+) T cells and TCR gamma delta(+) T cells remained unchanged by Treg depletion. We also documented a distinct population of IL-17A(+)TNF(+) TCR gamma delta(+)CD8(-) T cells in tumors, which were not affected by Treg depletion. We conclude that Treg depletion affects only conventional TCR alpha beta(+)CD8 alpha beta(+) T cells in intestinal tumors, while unconventional T cells and T cells in unaffected tissue are not altered. Immunotherapies aimed at depleting Treg from tumors may thus be a viable option for reinvigoration of conventional cytotoxic T cells with a Th1 cytokine profile.
|
|
| 14. |
- Szeponik, Louis
(author)
-
T cells in colon cancer; migration and effector functions
- 2022
-
Doctoral thesis (other academic/artistic)abstract
- Immune cells are recognised as one of the main players in the tumor microenvironment and targeted by many new cancer therapies. Regulatory T cells (Treg) can suppress tumor infiltrating lymphocytes which are associated with a better patient outcome. Additionally, unconventional T cells have the potential to kill tumor cells through T cell receptor-independent mechanisms and also in a non- major histocompatibility complex restricted manner. The aim of this thesis was to investigate how Treg can supress the T cell migration into intestinal tumors and what type of T cell populations are affected. Furthermore, we characterized different unconventional T cell populations in human colon cancer samples using mass cytometry. We used APCMin/+/DEREG mice to deplete Treg in intestinal tumors. We demonstrated that Treg inhibit the transendothelial migration of T cells into tumors dependent on the interaction of CXCR3 with its ligand CXCL10. Endothelial cells increased expression of CXCL10 when Treg were depleted in tumors. Furthermore, Treg inhibited the expression of endothelial neutral sphingomyelinase 2 (nSMase2) through TGF-β and other unknown soluble factors which resulted in reduced expression of adhesion molecules and chemokines, and decreased tumor infiltration of T cells. CD8αβ T cells were specifically affected by Treg depletion which increased their expression of Th1 related molecules, activation, and proliferation, while CD8αα T cells and γδ T cells were unaffected. In human tumors, exhausted mucosal associated invariant T (MAIT) cells were increased compared to unaffected tissue and none of the MAIT cell populations expressed high levels of activating natural killer cell receptors. In addition, γδ T cell subpopulations showed a great diversity, and some populations were patient specific. In conclusions, this thesis demonstrates that Treg depletion increases the migration of tumor infiltrating T cells associated with a Th1 response. This is partly mediated by nSMase2 inhibition in endothelial cells. Treg depletion could be a viable option to increase beneficial effector T cells in colorectal cancer patients.
|
|
