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In colon cancer, tumor progression and patient outcome is affected by the cytokine balance in the tumors. IFNγ, TNFα and Granzyme B expression are associated with favorable patient outcome, while high IL-17 expression is associated with... more
In colon cancer, tumor progression and patient outcome is affected by the cytokine balance in the tumors. IFNγ, TNFα and Granzyme B expression are associated with favorable patient outcome, while high IL-17 expression is associated with accelerated tumor progression. However, knowledge of the regulation and activation of unconventional T cell subsets in colon tumors is limited. The aim of this study was to characterize unconventional T cells in colon tumors and unaffected tissue, determine their capacity to produce cytokines affecting tumor progression as well as the In vitro cytotoxic capabilities of MAIT and γδ T cells. Using flow cytometry, we show that MAIT cells accumulate in colon tumors and that the frequencies of γδ T cells are reduced in the tumor epithelium. Using polyclonal stimulation, we show that IFNγ production by tumour infiltrating MAIT cells is impaired whilst tumour infiltrating γδ T have an increased expression of IFNγ, TNFα and Granzyme B. IL-17 expression was also elevated in tumour infiltrating γδ T cells, but at lower levels than the TH1 - associated cytokines. Tumor infiltrating MAIT cells had an exhausted (PD-1highTim-3+) phenotype compared to MAIT cells from unaffected tissue. Analyzing cytokine expression, we show that while no single molecule is lost the polyfunctional capacity of tumour infiltrating MAIT cells is decreased compared to MAIT cells from unaffected tissue. Altogether, this study shows that γδ T cells and MAIT cells contribute to the cytokine balance in colon tumors with a TH1 – dominated profile and that they have potent cytotoxic capacity, which may reduce tumor progression and improve patient outcome.
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Genetics, Algorithms, Human Genetics, Complementary and Alternative Medicine, Family, and 15 moreBiology, Linear models, Biological Sciences, DNA, Humans, Glaucoma, Female, Intraocular Pressure, Aged, Human Genome, Genotype, Adult, European Continental Ancestry Group, Genetic Association, and alleles
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... more
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 microenviro...
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The combination of 5-fluorouracil (5-FU) and leucovorin (LV) forms the chemotherapy backbone for patients with colorectal cancer. However, the LV administration is often standardized and not based on robust scientific data. To address... more
The combination of 5-fluorouracil (5-FU) and leucovorin (LV) forms the chemotherapy backbone for patients with colorectal cancer. However, the LV administration is often standardized and not based on robust scientific data. To address these issues, a randomized pharmacokinetics study was performed in patients with colon cancer. Thirty patients were enrolled, receiving 60, 200 or 500 mg/m2 LV as a single two-hour infusion. Blood, tumor, mucosa, and resection margin biopsies were collected. Folate concentrations were analyzed with LC-MS/MS and gene expression with qPCR. Data from a previous study where patients received LV as bolus injections were used as comparison. Saturation of methylenetetrahydrofolate (MeTHF) and tetrahydrofolate (THF) levels was seen after two-hour infusion and polyglutamated MeTHF + THF levels in tumors decreased with increasing LV dosage. The decrease was associated with decreased FPGS and increased GGH expression, which was not observed after LV bolus injecti...
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Background Colorectal cancer is a commonly diagnosed cancer worldwide. Unfortunately, many patients do not respond to standard chemotherapy treatments and develop disease relapse and metastases. Besides cancer cell specific genetic... more
Background Colorectal cancer is a commonly diagnosed cancer worldwide. Unfortunately, many patients do not respond to standard chemotherapy treatments and develop disease relapse and metastases. Besides cancer cell specific genetic changes, heterogeneity in the tumor microenvironment contribute to the clinical presentation of the disease and can potentially also influence drug resistance. By using a recently developed patient-derived scaffold method monitoring how a standardized reporter cancer cell line adapts to various microenvironments treated with chemotherapy, we wanted to clarify how individual patient specific microenvironments influence the chemotherapy response in colorectal cancer. Methods Surgically resected colorectal cancer specimens from 89 patients were decellularized to produce patient-derived scaffold, which were seeded with HT29 cells, cultured for 3 weeks, and treated with 5-fluorouracil. Gene expression changes of adapted and treated HT29 cells were monitored by...
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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... more
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 m...
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Additional file1: Table S1. Characteristics of the colon cancer patients included in mass cytometry analyses. Table S2. Characteristics of the colon cancer patients included in the survival analysis. Table S3. List of antibodies used in... more
Additional file1: Table S1. Characteristics of the colon cancer patients included in mass cytometry analyses. Table S2. Characteristics of the colon cancer patients included in the survival analysis. Table S3. List of antibodies used in mass cytometry experiments. Table S4. List of antibodies used in flow cytometry experiments. Figure S1. Gating strategy for mass cytometry experiments. Figure S2. Color overlay of all protein markers used in Fig. 1 on the UMAP plot. Figure S3. Expression of ICOS, OX-40, CD39, and CD56 in the different Phenograph clusters. Figure S4. Paired analysis of Phenograph cluster frequencies. Figure S5. Gating strategy for identification of Treg. Figure S6. Correlation between CD39 expression by Treg in different tissues.
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Inflammasomes are intracellular protein complexes whose activation results in proinflammatory cytokines. Inflammasomes are implicated in Crohn´s disease (CD) pathogenesis, yet the contribution of inflammasomes in intestinal epithelial... more
Inflammasomes are intracellular protein complexes whose activation results in proinflammatory cytokines. Inflammasomes are implicated in Crohn´s disease (CD) pathogenesis, yet the contribution of inflammasomes in intestinal epithelial cells (IECs) versus lamina propria (LP) macrophages is poorly understood. Whether inflammasome expression in intestinal tissue reflects the serum inflammatory protein profile of patients is also not known. We aimed to determine the intestinal cell types where inflammasome expression is increased in CD and if they correlate with the serum protein profile. RT-PCR and NanoString nCounter technology were used to characterize inflammasome gene expression in CD patients and controls. The mucosa, LP and IEC cell fractions and FACS-sorted cells were analyzed. Proximity extension assay with a 92-protein panel was used to determine the serum inflammatory protein profile. Compositional analysis was used to correlate ileum inflammasome gene expression with intesti...
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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... more
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 anti...
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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... more
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 high...
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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... more
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...
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Biology and Cell Biology
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... more
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 APCmin/+ 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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Colorectal cancer is the second most common cause of cancer‐related death worldwide and standardized therapies often fail to treat the more aggressive and progressive types of colorectal cancer. Tumor cell heterogeneity and influence from... more
Colorectal cancer is the second most common cause of cancer‐related death worldwide and standardized therapies often fail to treat the more aggressive and progressive types of colorectal cancer. Tumor cell heterogeneity and influence from the surrounding tumor microenvironment (TME) contribute to the complexity of the disease and large variability in clinical outcomes.
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Background Single nucleotide polymorphisms (SNPs) in DNA repair genes have a potential clinical value in predicting treatment outcomes. In the current study, we examined the association of SNPs in the genes XRCC1-rs25487, ERCC1-rs11615,... more
Background Single nucleotide polymorphisms (SNPs) in DNA repair genes have a potential clinical value in predicting treatment outcomes. In the current study, we examined the association of SNPs in the genes XRCC1-rs25487, ERCC1-rs11615, ERCC2-rs238406, and ERCC2-rs13181 with colorectal cancer (CRC) risk, relapse-free survival (RFS), overall survival (OS), and toxicity during chemotherapy. Methods SNPs were analysed in 590 CRC cases and 300 controls using TaqMan technology. The association of SNPs with CRC risk and toxicity during chemotherapy was analysed using Chi2 test. The Kaplan–Meier method and log-rank test was used to measure the effects of the SNPs on RFS and OS. Results The CC genotype of ERCC2-rs238406 and the ERCC2-rs13181 C allele were associated with a significantly increased risk of CRC. The ERCC1-rs11615 genotype T/T was associated with stomatitis in adjuvant chemotherapy (p = 0.03). Also, more patients with the ERCC2-rs13181 C allele needed dose reduction compared to...
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3550Background: 5-fluorouracil (5-FU) with the folate pro-drug leucovorin (LV) has long been backbone of chemotherapy for colorectal cancer (CRC). Low expression of folate-related genes may lead to...
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Chronic intestinal injury after pelvic radiotherapy affects countless cancer survivors worldwide. A comprehensive understanding of the long-term injury dynamics is prevented in available animal models. With linear accelerators that are... more
Chronic intestinal injury after pelvic radiotherapy affects countless cancer survivors worldwide. A comprehensive understanding of the long-term injury dynamics is prevented in available animal models. With linear accelerators that are used to treat cancer in patients, we irradiated a small volume encompassing the colorectum in mice with four fractions of 8 Gy per fraction. We then determined the long-term dynamics of mucosal injury, repair, and the duration of inflammation. We show that crypt fission, not cell proliferation, is the main long-term mechanism for rescuing crypt density after irradiation, and provides a potentially wide window for clinical interventions. Persisting macrophage aggregations indicate a chronic mucosal inflammation. A better understanding as to how crypt fission is triggered and why it fails to repair fully the mucosa may help restore bowel health after pelvic radiotherapy. Moreover, anti-inflammatory interventions, even if implemented long after completed...
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Chemistry, Cytotoxicity, Medicine, Perforin, Granzyme, and 3 moreMAIT Cells, tumor immunity, and degranulation
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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. This national population-based... more
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. 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. 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 t...
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Oncology, Cancer, Medicine, Colorectal cancer, Population, and 15 moreHumans, Internal Medicine, Female, Male, Aged, Middle Aged, Practice Guidelines, Colorectal Neoplasms, Combined Modality Therapy, Guideline Adherence, Neoplasm grading, Neoplasm staging, Neoplasm metastasis, Colonic Neoplasms, and Population surveillance
Background 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... more
Background 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. Methods and Results TP gene expression was analyzed by real-time quantitative PCR in tumor and mucosa samples from 254 patients. TP gene expression in tumors correlated with lymph node staging, with higher expression relating to a higher number of positive nodes and a worse N-stage. Higher TP expression was also associated with a worse histological tumor grade. Patients with rectal cancer had significantly higher TP expression in mucosa and tumors compared with patients having colon cancer. Conclusion Higher intratumoral TP expression appears to be related to a worse N stage, and thus, with a worse prognosis. TP gene expression measured in a preoperative biopsy could be of interest in preoperative staging.
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To evaluate the outcome of patients treated for appendiceal abscess, and managed either conservatively or surgically, and to describe the short and long-term outcome as well as incidence of interval appendicectomy in those treated... more
To evaluate the outcome of patients treated for appendiceal abscess, and managed either conservatively or surgically, and to describe the short and long-term outcome as well as incidence of interval appendicectomy in those treated conservatively. Retrospective study. University hospital, Sweden. Ninety-three patients with the diagnosis of appendiceal abscess, 50 treated conservatively and 43 who were operated on, with a mean age of 46 (14-93) years. Mean (range) follow-up for patients operated on was 65 (11-135) and for those treated conservatively 66 (6-136) months. Course of acute disease, recorded complications, recurrence of appendicitis and incidence of interval appendicectomy during follow-up. The duration of pain before admission was 4 (0.5-82) days for those operated on and 7 (2-60) days for those treated conservatively. A palpable mass was more common in the conservatively managed group. Complications were common among patients who were operated on. No interval appendicectomies were done during the second half of the study period. 4 of the patients treated conservatively (8%) had an underlying tumour diagnosed at follow-up. Operative management of patients with appendiceal masses seems to be associated with a high risk of postoperative complications and the risk of a more extensive surgical procedure. If possible, a conservative approach should be advocated. Because of inaccurate radiological imaging during the acute phase and the risk of an underlying malignancy, routine follow-up is necessary. Routine interval appendicectomy cannot be recommended.
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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... more
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-1highTim-3+CD39+ terminally exhausted phenotype and an increased proliferation accumulate in colon tumors. The exhauste...
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The enzyme thymidine phosphorylase (TYMP) has tumor-promoting functions and its expression is often elevated in tumors. TYMP gene expression in tumorous and mucosal tissues was assessed using real-time polymerase chain reaction, in a... more
The enzyme thymidine phosphorylase (TYMP) has tumor-promoting functions and its expression is often elevated in tumors. TYMP gene expression in tumorous and mucosal tissues was assessed using real-time polymerase chain reaction, in a study of patients with rectal cancer where chemotherapy and radiotherapy were given sequentially. TYMP levels decreased after chemotherapy. For patients given radiotherapy, there was a significant increase in TYMP expression comparing biopsies before and after radiotherapy. The increase was also observed in the mucosa, although it was less pronounced. Cancer treatment alters gene expression in tumor and adjacent mucosa of patients with rectal cancer. Chemotherapy may cause a decrease in TYMP gene expression, whereas radiotherapy, given as adjuvant treatment, causes a significant increase in expression. These results are of importance when interpreting TYMP expression data in rectal cancer and may be of clinical interest as TYMP participates in the activ...
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The tumour differentiation grade has been shown by numerous multivariate analyses to be a stage-independent prognostic factor in colorectal cancer. The aim of this study was to explore the importance of differentiation grading for the... more
The tumour differentiation grade has been shown by numerous multivariate analyses to be a stage-independent prognostic factor in colorectal cancer. The aim of this study was to explore the importance of differentiation grading for the staging of colorectal cancer and how it relates to the components of the TNM system. The study was a retrospective single-centre analysis of all patients undergoing surgical resection for colorectal cancer during the period 2002-2007 (n = 1239). The clinical parameters and pathology data of overall stage, differentiation grade, local tumour (T)-stage and metastasis status (M-stage) were included as well as the lymph node count of both assessed and metastatic nodes. The differentiation grade was correlated with demography, overall stage and each component of the TNM staging system. The correlation between differentiation grade and N-stage was also explored for the separate T-stages. The tumour differentiation grade correlated significantly with the overall TNM stage (p &amp;amp;amp;amp;amp;amp;lt; 0.0001). The grade significantly correlated with the T-stage and the risk of having lymph node metastasis (p &amp;amp;amp;amp;amp;amp;lt; 0.0001). A high grade was associated with a higher positive lymph node count in stage III disease (p &amp;amp;amp;amp;amp;amp;lt; 0.0002). For the T-stages, the risk of node metastasis was significantly linked to the tumour grade. A low grade (G1) T2 had a 17% risk of lymph node metastasis compared to a 44% risk for a high grade (G4) T2. Tumour differentiation is an important prognostic factor. It correlates significantly with the overall stage of the TNM system and also to each of its components. The risk of having lymph node metastasis for each T-stage also correlates with the tumour grade. The findings can be of importance in postoperative risk assessment or when considering local resection procedures like TEM.