Immune status is prognostic for poor survival in colorectal cancer patients and is associated with tumour hypoxia.
Ontology highlight
ABSTRACT: Background
Immunohistochemical quantification of the immune response is prognostic for colorectal cancer (CRC). Here, we evaluate the suitability of alternative immune classifiers on prognosis and assess whether they relate to biological features amenable to targeted therapy.Methods
Overall survival by immune (CD3, CD4, CD8, CD20 and FOXP3) and immune-checkpoint (ICOS, IDO-1 and PD-L1) biomarkers in independent CRC cohorts was evaluated. Matched mutational and transcriptomic data were interrogated to identify associated biology.Results
Determination of immune-cold tumours by combined low-density cell counts of CD3, CD4 and CD8 immunohistochemistry constituted the best prognosticator across stage II-IV CRC, particularly in patients with stage IV disease (HR 1.98 [95% CI: 1.47-2.67]). These immune-cold CRCs were associated with tumour hypoxia, confirmed using CAIX immunohistochemistry (P = 0.0009), which may mediate disease progression through common biology (KRAS mutations, CRIS-B subtype and SPP1 mRNA overexpression).Conclusions
Given the significantly poorer survival of immune-cold CRC patients, these data illustrate that assessment of CD4-expressing cells complements low CD3 and CD8 immunohistochemical quantification in the tumour bulk, potentially facilitating immunophenotyping of patient biopsies to predict prognosis. In addition, we found immune-cold CRCs to associate with a difficult-to-treat, poor prognosis hypoxia signature, indicating that these patients may benefit from hypoxia-targeting clinical trials.
SUBMITTER: Craig SG
PROVIDER: S-EPMC7555485 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BACKGROUND:High-level plasma 25-hydroxyvitamin D [25(OH)D] has been associated with lower colorectal cancer incidence and mortality. Considering evidence indicating immunomodulatory effects of vitamin D, we hypothesised that survival benefits from high systemic vitamin D level might be stronger for colorectal carcinoma with lower immune response to tumour. METHODS:Using 869 colon and rectal cancer cases within the Nurses' Health Study and Health Professionals Follow-up Study, we assessed the prognostic association of postdiagnosis 25(OH)D score [derived from diet and lifestyle variables to predict plasma 25(OH)D level] in strata of levels of histopathologic lymphocytic reaction. The Cox proportional hazards regression model was adjusted for potential confounders, including microsatellite instability, CpG island methylator phenotype, LINE-1 methylation, PTGS2 (cyclooxygenase-2) expression and KRAS, BRAF and PIK3CA mutations. RESULTS:The association of postdiagnosis 25(OH)D score with colorectal cancer-specific mortality differed by levels of peritumoural lymphocytic reaction (pinteraction = 0.001). Multivariable-adjusted mortality hazard ratios for a quintile-unit increase of 25(OH)D score were 0.69 [95% confidence interval (CI), 0.54-0.89] in cases with negative/low peritumoural lymphocytic reaction, 1.08 (95% CI, 0.93-1.26) in cases with intermediate peritumoural reaction and 1.25 (95% CI, 0.75-2.09) in cases with high peritumoural reaction. The survival association of the 25(OH)D score did not significantly differ by Crohn's-like lymphoid reaction, intratumoural periglandular reaction or tumour-infiltrating lymphocytes. CONCLUSIONS:The association between the 25(OH)D score and colorectal cancer survival is stronger for carcinomas with lower peritumoural lymphocytic reaction. Our results suggesting interactive effects of vitamin D and immune response may contribute to personalised dietary and lifestyle intervention strategies.
| S-EPMC6195453 | biostudies-literature
Project description:Background: Acute myeloid leukemia (AML) is a heterogeneous malignant disease. SLC25A1, the gene encoding mitochondrial carrier subfamily of solute carrier proteins, was reported to be overexpressed in certain solid tumors. However, its expression and value as prognostic marker has not been assessed in AML. Methods: We retrieved RNA profile and corresponding clinical data of AML patients from the Beat AML, TCGA, and TARGET databases (TARGET_AML). Patients in the TCGA cohort were well-grouped into two group based on SLC25A1 and differentially expressed genes were determined between the SLC25A1 high and low group. The expression of SLC25A1 was validated with clinical samples. The survival and apoptosis of two AML cell lines were analyzed with SLC25A1 inhibitor (CTPI-2) treatment. Cox and the least absolute shrinkage and selection operator (LASSO) regression analyses were applied to Beat AML database to identify SLC25A1-associated genes for the construction of a prognostic risk-scoring model. Survival analysis was performed by Kaplan-Meier and receiver operator characteristic curves. Results: Our analysis revealed that high expressed level of SLC25A1 in AML patients correlates with unfavorable prognosis. Moreover, SLC25A1 expression was positively associated with metabolism activity. We further demonstrated that the inhibition of SLC25A1 could inhibit the proliferation and increase the apoptosis of AML cells. In addition, a panel of SLC25A1-associated genes, was identified to construct a prognostic risk-scoring model. This SLC25A1-associated prognostic signature (SPS) is an independent risk factor with high area under curve (AUC) values of receiver operating characteristic (ROC) curves. A high SPS in leukemia patients is associated with poor survival. A Prognostic nomogram including the SPS and other clinical parameters, was constructed and its predictive efficiency was confirmed. Conclusion: We have successfully established a SPS prognostic model that predict outcome and risk stratification in AML. This risk model can be used as an independent biomarker to assess prognosis of AML.
| S-EPMC9852877 | biostudies-literature
Project description:Hypoxia is an extensively investigated condition due to its contribution to various pathophysiological processes including cancer progression and metastasis formation. MicroRNAs (miRNAs) are well-known post-transcriptional gene expression regulators. However, their contribution to molecular response to hypoxia is highly dependent on cell/tissue types and causes of hypoxia. One of the most important examples is colorectal cancer, where no consensus on hypoxia-regulated miRNAs has been reached so far. In this work, we applied integrated mRNA and small RNA sequencing, followed by bioinformatics analysis, to study the landscape of hypoxia-induced miRNA and mRNA expression alterations in human colorectal cancer cell lines (HT-29 and Caco-2). A hypoxic microenvironment was chemically modeled using two different treatments: cobalt(II) chloride and oxyquinoline. Only one miRNA, hsa-miR-210-3p, was upregulated in all experimental conditions, while there were nine differentially expressed miRNAs under both treatments within the same cell line. Further bioinformatics analysis revealed a complex hypoxia-induced regulatory network: hypoxic downregulation of hsa-miR-148a-3p led to the upregulation of its two target genes, ITGA5 and PRNP, which was shown to be a factor contributing to tumor progression and poor survival in colorectal cancer patients.
| S-EPMC8202010 | biostudies-literature
Project description:BackgroundIt is widely accepted that the oxygen level in tumor tissue is significantly lower than the adjacent normal tissue, thus termed hypoxia. Intratumoral hypoxia represents a major driving force in cancer progression, recurrence, metastasis, and decreased survival. Though multiple gene signatures reflect the complex cellular response to hypoxia have been established in several cancer types such as head and neck, breast, and lung cancers, the hypoxic panorama in colorectal cancer (CRC) remains poorly understood.MethodsA hypoxic signature constituted by a total of 356 genes, including canonical hypoxia-responsive ADM, ANGPTL4, CA9, and VEGFA, was established based on systemic literature search. A total of 1,730 CRC samples across four independent cohorts were used for nonnegative matrix factorization clustering and subtyping. Prognosis, molecular signatures, pathways, and tumor-infiltrating lymphocytes were compared between the subtypes.ResultsCRCs mainly fell into two subgroups, one indicated as hypoxia and the other one designated as normoxia. Hypoxia was correlated with poor outcomes in CRC and will increase the risk of a subset of stage II patients to the level of normoxic stage III. Additionally, hypoxia was closely associated with activation of RAS signaling pathway independent of KRAS mutation. More M2 macrophage infiltration was another hypoxic marker indicated that subsets of patients with high M2 macrophages may benefit from macrophage-targeting therapy.ConclusionsThese findings will facilitate the development of a hypoxia-oriented therapy strategy to enhance the treatment effect in the near future.
| S-EPMC7714992 | biostudies-literature
Project description:The present study was to investigate the clinical significance of peroxiredoxin 2 (PRDX2), an oncoenzyme, in the development and progression of colorectal cancer(CRC).We found levels of PRDX2 mRNA and protein were higher in CRC cell lines than in normal human colonic epithelial cells. PRDX2 expression was significantly up-regulated in CRC lesions compared with that in the adjacent noncancerous tissues. CRC tissues from 148 of 226 (65.5%) patients revealed high level of PRDX2 protein expression in contrast to only 13 of 226 (5.8%) PRDX2 strong staining cases in the adjacent noncancerous tissues. Increased expression of PRDX2 protein was significantly associated with poor tumor differentiation (p = 0.001), advanced local invasion (p = 0.046), increased lymph node metastasis (p = 0.008), and advanced TNM stage (p = 0.020). Patients with higher PRDX2 expression had a significantly shorter disease-free survival and worse disease-specific survival than those with low expression. Importantly, PRDX2 up-regulation was an independent prognostic indicator for stage I-III, early stage (stage I-II) and advanced stage (stage III) patients. In conclusion, our findings suggest PRDX2 up-regulation correlates with tumor progression and could serve as a useful marker for the prognosis of CRC.
| S-EPMC5362467 | biostudies-literature
Project description:Prognosis in colorectal cancer patients is quite variable, even after adjustment for clinical parameters such as disease stage and microsatellite instability status. It is possible that the psychological distress experienced by patients, including anxiety and depression, may be correlated with poor prognosis. In the present study, we hypothesize that genetic variations within three genes biologically linked to the stress response, namely serotonin transporter (SLC6A4), brain-derived neurotrophic factor (BDNF), and arginine vasopressin receptor (AVPR1B) genes are associated with prognosis in colorectal cancer patients. We used a population-based cohort of 280 patients who were followed for up to 12.5 years after diagnosis. Our multivariate analysis showed that a tagSNP in the SLC6A4 gene (rs12150214) was a predictor of shorter overall survival (HR: 1.572, 95%CI: 1.142-2.164, p = 0.005) independent of stage, age, grade and MSI status. Additionally, a multivariate analysis using the combined genotypes of three polymorphisms in this gene demonstrated that the presence of any of the minor alleles at these polymorphic loci was an independent predictor of both shorter overall survival (HR: 1.631, 95%CI: 1.190-2.236, p = 0.002) and shorter disease specific survival (HR: 1.691, 95%CI: 1.138-2.512, p = 0.009). The 5-HTT protein coded by the SLC6A4 gene has also been implicated in inflammation. While our results remain to be replicated in other patient cohorts, we suggest that the genetic variations in the SLC6A4 gene contribute to poor survival in colorectal cancer patients.
| S-EPMC3404081 | biostudies-literature
Project description:BackgroundThere is an insufficient number of reliable prognostic and response predictive biomarkers in colorectal cancer (CRC) management. In a previous study, we found that high tumour tissue expression of tumour-associated trypsin inhibitor (TATI) correlated with liver metastasis and an impaired prognosis in CRC. The aim of this study was to investigate the prognostic validity of serum TATI (s-TATI) in CRC. We further assessed the prognostic value of carcino-embryonic antigen in serum (s-CEA) and the interrelationship between s-TATI and TATI in tissue (t-TATI).MethodsUsing an immunofluorometric assay, s-TATI levels were analysed in 334 preoperatively collected serum samples from patients with CRC. Spearman's Rho and Chi-square test were used for analysis of correlations between s-TATI and clinicopathological parameters, s-CEA and t-TATI. Kaplan-Meier analysis and Cox uni- and multivariate regression analysis were used to estimate disease free survival (DFS) and overall survival (OS) according to quartiles of s-TATI and cut-offs derived from ROC-analysis of s-TATI and s-CEA.ResultsIncreased levels of s-TATI were associated with a reduced DFS (HR = 2.00; 95% CI 1.40-2.84, P < 0.001) and OS (HR = 2.40; 95% CI 1.74-3.33, P < 0.001). (HR = 2.89; 95% CI 1.96-4.25). This association remained significant in multivariate analysis. The association for OS remained significant in multivariate analysis (HR = 1.51; 95% CI 1.03-2.22, P = 0.034 for DFS and HR = 1.78; 95% CI 1.25-2.53, P = 0.001 for OS). There was no significant association between s-TATI and t-TATI. The prognostic value of s-CEA was also evident, but somewhat weaker than for s-TATI.ConclusionsHigh preoperative s-TATI levels predict a poor prognosis in patients with CRC, and the prognostic value is independent of established prognostic parameters and t-TATI expression. These data suggest that s-TATI might be a useful marker for prognostic stratification in CRC.
| S-EPMC2946315 | biostudies-literature
Project description:BACKGROUND:SPINK4 is known as a gastrointestinal peptide in the gastrointestinal tract and is abundantly expressed in human goblet cells. The clinical significance of SPINK4 in colorectal cancer (CRC) is largely unknown. METHODS:We retrieved the expression data of 1168 CRC patients from 3 Gene Expression Omnibus (GEO) datasets (GSE24551, GSE39582, GSE32323) and The Cancer Genome Atlas (TCGA) to compare the expression level of SPINK4 between CRC tissues and normal colorectal tissues and to evaluate its value in predicting the survival of CRC patients. At the protein level, these results were further confirmed by data mining in the Human Protein Atlas and by immunohistochemical staining of samples from 81 CRC cases in our own center. RESULTS:SPINK4 expression was downregulated in CRC compared with that in normal tissues, and decreased SPINK4 expression at both the mRNA and protein levels was associated with poor prognosis in CRC patients from all 3 GEO datasets, the TCGA database and our cohort. Additionally, lower SPINK4 expression was significantly related to higher TNM stage. Moreover, in multivariate regression, SPINK4 was confirmed as an independent indicator of poor survival in CRC patients in all databases and in our own cohort. CONCLUSIONS:We concluded that reduced expression of SPINK4 relates to poor survival in CRC, functioning as a novel indicator.
| S-EPMC6938003 | biostudies-literature
Project description:Rationale: Epigenetic mechanisms are fundamental processes that can modulate gene expression, allowing cellular adaptation to environmental conditions. Hypoxia is an important factor known to initiate the metastatic cascade in cancer, activating cell motility and invasion by silencing cell adhesion genes. G9a is a histone methyltransferase previously shown to accumulate in hypoxic conditions. While its oncogenic activity has been previously reported, not much is known about the role G9a plays in the hypoxia-mediated metastatic cascade. Methods: The role of G9a in cell motility in hypoxic condition was determined by inhibiting G9a either by short-hairpin mediated knock down or pharmacologically using a small molecule inhibitor. Through gene expression profiling, we identified CDH10 to be an important G9a target that regulates breast cancer cell motility. Lung metastasis assay in mice was used to determine the physiological significance of G9a. Results: We demonstrate that, while hypoxia enhances breast cancer migratory capacity, blocking G9a severely reduces cellular motility under both normoxic and hypoxic conditions and prevents the hypoxia-mediated induction of cellular movement. Moreover, inhibition of G9a histone methyltransferase activity in mice using a specific small molecule inhibitor significantly reduced growth and colonisation of breast cancer cells in the lung. We identify the type-II cadherin CDH10 as being a novel hypoxia-dependent gene, directly repressed by G9a through histone methylation. CDH10 overexpression significantly reduces cellular movements in breast cancer cell lines and prevents the hypoxia-mediated increase in cell motility. In addition, we show that CDH10 expression is prognostic in breast cancer and that it is inversely correlated to EHMT2 (G9a) transcript levels in many tumor-types, including breast cancer. Conclusion: We propose that G9a promotes cellular motility during hypoxic stress through the silencing of the cell adhesion molecule CDH10 and we describe CDH10 as a novel prognostic biomarker for breast cancer.
| S-EPMC7150496 | biostudies-literature
Project description:BackgroundCOP9 signalosome subunit 2 (CSN2) is believed to be involved in human cancer, but its prognostic significance in colorectal cancer (CRC) has not been elucidated.Patients and methodsWe retrospectively analyzed the expression of CSN2 andCD8+ tumor-infiltrating lymphocytes (TILs), and mismatch repair (MMR) status in 267 paraffin-embedded specimens using immunohistochemistry in a training cohort. A number of risk factors were used to form nomograms to evaluate survival, and Harrell's concordance index (C-index) was used to evaluate the predictive accuracy. Further validation was performed in an independent cohort of 238cases.ResultsLow CSN2 expression and a low number of CD8 + TILs were significantly associated with diminished disease-free survival (DFS) and overall survival (OS) in CRC patients, and patients with MMR-deficient CRC had enhanced DFS and OS. Moreover, the multivariate Cox analysis identified CSN2, CD8 + TILs, and MMR status as independent prognostic factors for DFS and OS. Using these three markers and four clinicopathological risk variables, two nomograms were constructed and validated for predicting DFS and OS (C-index: training cohort, 0.836 (95% CI:0.804-0.868) and 0.841 (0.808-0.874), respectively; validation cohort, 0.801 (0.760-843) and 0.843 (0.806-0.881), respectively).ConclusionsCSN2, CD8+ TILs, and MMR status were independent prognostic factors. The nomograms could be used to generate individualized predictions for DFS and OS.
| S-EPMC6080638 | biostudies-literature