Shaping immune landscape of colorectal cancer by cholesterol metabolites
Ontology highlight
ABSTRACT:
SUBMITTER: Prof. Chenqi Xu
PROVIDER: S-SCDT-10_1038-S44321-023-00015-9 | biostudies-other |
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Cancer immunotherapies have achieved unprecedented success in clinic, but they remain largely ineffective in some major types of cancer, such as colorectal cancer with microsatellite stability (MSS CRC). It is therefore important to study tumor microenvironment of resistant cancers for developing new intervention strategies. In this study, we identify a metabolic cue that determines the unique immune landscape of MSS CRC. Through secretion of distal cholesterol precursors, which directly activate RORγt, MSS CRC cells can polarize T cells toward Th17 cells that have well-characterized pro-tumor functions in colorectal cancer. Analysis of large human cancer cohorts revealed an asynchronous pattern of the cholesterol biosynthesis in MSS CRC, which is responsible for the abnormal accumulation of distal cholesterol precursors. Inhibiting the cholesterol biosynthesis enzyme Cyp51, by pharmacological or genetic interventions, reduced the levels of intratumoral distal cholesterol precursors and suppressed tumor progression through a Th17-modulation mechanism in preclinical MSS CRC models. Our study therefore reveals a novel mechanism of cancer-immune interaction and an intervention strategy for the difficult-to-treat MSS CRC.
| S-EPMC10897227 | biostudies-literature
Project description:Cancer immunotherapies have achieved unprecedented success in clinic, but they remain largely ineffective in some major types of cancer, such as colorectal cancer with microsatellite stability (MSS CRC) (Picard et al., 2020). It is therefore important to study tumor microenvironment of resistant cancers for developing new intervention strategies. In this study, we identify a metabolic cue that determines the unique immune landscape of MSS CRC. Through secretion of distal cholesterol precursors, which directly activate RORgt, MSS CRC cells can polarize T cells toward Th17 cells that have well-characterized pro-tumor functions in colorectal cancer. Analysis of large human cancer cohorts revealed an asynchronous pattern of the cholesterol biosynthesis in MSS CRC, which is responsible for the abnormal accumulation of distal cholesterol precursors. Inhibiting the cholesterol biosynthesis enzyme Cyp51 by ketoconazole, a clinically approved drug, reduced the levels of intratumoral distal cholesterol precursors and suppressed tumor progression through a Th17-modulation mechanism in preclinical MSS CRC models. Our study therefore reveals a novel immune-modulation mechanism of oncometabolites and an invention strategy for the difficult-to-treat MSS CRC.
2023-12-02 | GSE249124 | GEO
Project description:Cancer immunotherapies have achieved unprecedented success in clinic, but they remain largely ineffective in some major types of cancer, such as colorectal cancer with microsatellite stability (MSS CRC) (Picard et al., 2020). It is therefore important to study tumor microenvironment of resistant cancers for developing new intervention strategies. In this study, we identify a metabolic cue that determines the unique immune landscape of MSS CRC. Through secretion of distal cholesterol precursors, which directly activate RORgt, MSS CRC cells can polarize T cells toward Th17 cells that have well-characterized pro-tumor functions in colorectal cancer. Analysis of large human cancer cohorts revealed an asynchronous pattern of the cholesterol biosynthesis in MSS CRC, which is responsible for the abnormal accumulation of distal cholesterol precursors. Inhibiting the cholesterol biosynthesis enzyme Cyp51 by ketoconazole, a clinically approved drug, reduced the levels of intratumoral distal cholesterol precursors and suppressed tumor progression through a Th17-modulation mechanism in preclinical MSS CRC models. Our study therefore reveals a novel immune-modulation mechanism of oncometabolites and an invention strategy for the difficult-to-treat MSS CRC.
2023-11-26 | GSE248570 | GEO
Project description:Shaping immune landscape of colorectal cancer by cholesterol metabolites [BALB/c]
| PRJNA1044794 | ENA
Project description:While the clinical importance of CD8+ and CD3+ cells in colorectal cancer (CRC) is well established, the impact of other immune cell subsets is less well described. We sought to provide a detailed overview of the immune landscape of CRC in the largest study to date in terms of patient numbers and in situ analyzed immune cell types. Tissue microarrays from 536 patients were stained using multiplexed immunofluorescence panels, and fifteen immune cell subclasses, representing adaptive and innate immunity, were analyzed. Overall, therapy-naïve CRC patients clustered into an 'inflamed' and a 'desert' group. Most T cell subsets and M2 macrophages were enriched in the right colon (p-values 0.046-0.004), while pDC cells were in the rectum (p = 0.008). Elderly patients had higher infiltration of M2 macrophages (p = 0.024). CD8+ cells were linked to improved survival in colon cancer stages I-III (q = 0.014), while CD4+ cells had the strongest impact on overall survival in metastatic CRC (q = 0.031). Finally, we demonstrated repopulation of the immune infiltrate in rectal tumors post radiation, following an initial radiation-induced depletion. This study provides a detailed analysis of the in situ immune landscape of CRC paving the way for better diagnostics and providing hints to better target the immune microenvironment.
| S-EPMC8583221 | biostudies-literature
Project description:BackgroundKRAS gene is the most common type of mutation reported in colorectal cancer (CRC). KRAS mutation-mediated regulation of immunophenotype and immune pathways in CRC remains to be elucidated.Methods535 CRC patients were used to compare the expression of immune-related genes (IRGs) and the abundance of tumor-infiltrating immune cells (TIICs) in the tumor microenvironment between KRAS-mutant and KRAS wild-type CRC patients. An independent dataset included 566 cases of CRC and an in-house RNA sequencing dataset were served as validation sets. An in-house dataset consisting of 335 CRC patients were used to analyze systemic immune and inflammatory state in the presence of KRAS mutation. An immue risk (Imm-R) model consist of IRG and TIICs for prognostic prediction in KRAS-mutant CRC patients was established and validated.ResultsNF-κB and T-cell receptor signaling pathways were significantly inhibited in KRAS-mutant CRC patients. Regulatory T cells (Tregs) was increased while macrophage M1 and activated CD4 memory T cell was decreased in KRAS-mutant CRC. Prognosis correlated with enhanced Tregs, macrophage M1 and activated CD4 memory T cell and was validated. Serum levels of hypersensitive C-reactive protein (hs-CRP), CRP, and IgM were significantly decreased in KRAS-mutant compared to KRAS wild-type CRC patients. An immune risk model composed of VGF, RLN3, CT45A1 and TIICs signature classified CRC patients with distinct clinical outcomes.ConclusionsKRAS mutation in CRC was associated with suppressed immune pathways and immune infiltration. The aberrant immune pathways and immune cells help to understand the tumor immune microenvironments in KRAS-mutant CRC patients.
| S-EPMC7789428 | biostudies-literature
Project description:BackgroundColorectal cancer (CRC) is a highly heterogeneous cancer. This heterogeneity has an impact on the efficacy of immunotherapy. Long noncoding RNAs (lncRNAs) have been found to play regulatory functions in cancer immunity. However, the global landscape of immune-derived lncRNA signatures has not yet been explored in colorectal cancer.MethodsIn this study, we applied DESeq2 to identify differentially expressed lncRNAs in colon cancer. Next, we performed an integrative analysis to globally identify immune-driven lncRNA markers in CRC, including immune-associated pathways, tumor immunogenomic features, tumor-infiltrating immune cells, immune checkpoints, microsatellite instability (MSI) and tumor mutation burden (TMB).ResultsWe also identified dysregulated lncRNAs, such as LINC01354 and LINC02257, and their clinical relevance in CRC. Our findings revealed that the differentially expressed lncRNAs were closely associated with immune pathways. In addition, we found that RP11-354P11.3 and RP11-545G3.1 had the highest association with the immunogenomic signature. As a result, these signatures could serve as markers to assess immunogenomic activity in CRC. Among the immune cells, resting mast cells and M0 macrophages had the highest association with lncRNAs in CRC. The AC006129.2 gene was significantly associated with several immune checkpoints, for example, programmed cell death protein 1 (PD-1) and B and T lymphocyte attenuator (BTLA). Therefore, the AC006129.2 gene could be targeted to regulate the condition of immune cells or immune checkpoints to enhance the efficacy of immunotherapy in CRC patients. Finally, we identified 15 immune-related lncRNA-generated open reading frames (ORFs) corresponding to 15 cancer immune epitopes.ConclusionIn conclusion, we provided a genome-wide immune-driven lncRNA signature for CRC that might provide new insights into clinical applications and immunotherapy.
| S-EPMC10900961 | biostudies-literature
Project description:Colorectal cancer (CRC) has the characteristics of high morbidity and mortality. LncRNA not only participates in the progression of CRC through genes and transcription levels, but also regulates the tumor microenvironment and leads to the malignant phenotype of tumors. Therefore, we identified immune-related LncRNAs for the construction of clinical prognostic model. We searched The Cancer Genome Atlas (TCGA) database for original data. Then we identified differentially expressed irlncRNA (DEirlncRNA), which was paired and verified subsequently. Next, univariate analysis, Lasso and Cox regression analysis were performed on the DEirlncRNA pair. The ROC curve of the signature was drawn, and the optimal cut-off value was found. Then the cohort was divided into a high-risk and a low-risk group. Finally, we re-evaluated the signature from different perspectives. A total of 16 pairs of DEirlncRNA were included in the construction of the model. After regrouping according to the cut-off value of 1.275, the high-risk group showed adverse survival outcomes, progressive clinicopathological features, specific immune cell infiltration status, and high sensitivity to some chemotherapy drugs. In conclusion, we constructed a signature composed of immune-related LncRNA pair with no requirement of the specific expression level of genes, which shows promising clinical predictive value in CRC patients.
| S-EPMC8381735 | biostudies-literature
Project description:To define differences in tumor microenvironment (TME) immune phenotypes between right and left colorectal cancers (CRCs) and explore their therapeutic implications. Gene expression profiling and clinical characteristics of patients with CRC were retrieved from The Cancer Genome Atlas data portal. Immune cell infiltration was estimated based on single-sample gene set enrichment analysis. CRCs tissue microarrays (TMAs) containing 90 consecutive cases of surgical samples were used for validation. Expression of CD8A and VEGFA was confirmed by immunohistochemistry (IHC) analysis with TMAs, and overall survival (OS) was analyzed. Expression profiling data demonstrated that CRC immune microenvironment from right side tumor was characterized as increased infiltration of immune cells with enhanced cytotoxic function, based on higher cytotoxic activity scores (CYT) and interferon-γ signatures. Expression of VEGFA, which could be neutralized by bevacizumab, was associated with decreased levels of activated CD8+ T-cells, Th1 cells, and PRF1 expression on the right side, but not on the left side. IHC analysis of TMAs further confirmed an inverse correlation between CD8A and VEGFA expression, and revealed a favorable OS for patients with CD8AHiVEGFALo disease among right-side CRCs. For the left side, higher CD56bright natural killer cell infiltration and active 4-1BB/IFN-ɑ signaling, which could providing a favorable condition for cetuximab-mediated antibody-dependent cell-mediated cytotoxicity effect, was present in a cohort with extended OS. In the TME, features of immune phenotype sidedness were identified, providing an implication for differential responses to bevacizumab/cetuximab treatment. In addition, a new avenue for innovative experimental design and combinational immunotherapy to treat CRC patients was suggested.
| S-EPMC6048410 | biostudies-literature
Project description:BackgroundThe tumor microenvironment plays an essential role in the therapeutic response to immunotherapy. It is necessary to identify immune cell infiltration (ICI) subtypes for evaluating prognosis and therapeutic benefits. This study aimed to evaluate the ICI score as an effective prognostic biomarker for immune response.MethodsThe cell-type identification by estimating relative subsets of RNA transcripts and the estimation of stromal and immune cells in malignant tumors using expression methods were used to analyse ICI landscapes in 161 colorectal cancer (CRC) samples with patients' clinical and prognostic data, RNA sequencing data, and whole-exome sequencing data from the Sixth Affiliated Hospital, Sun Yat-sen University (Guangzhou, China). Statistical analysis and data processing were conducted to calculate ICI scores, and to analyse the prognosis of CRC patients with different ICI scores and other features. A similar analysis with RNA sequencing and clinical data of colon adenocarcinoma (COAD) samples from The Cancer Genome Atlas (TCGA) database was conducted to confirm the correctness of the findings.ResultsThe high-ICI score group with a better prognosis (hazard ratio [HR], 2.19; 95% confidence interval [CI], 1.03-4.64; log-rank test, P = 0.036) was characterized by the increased tumor mutational burden and interleukin-17 (IL-17) signaling pathway. Significant differences in the prognosis and the expression levels of immune checkpoints and chemokine marker genes were found between the two ICI score groups. For COAD samples from TCGA, the results also showed a significant difference in patients' prognosis between the two ICI score groups (HR, 1.72; 95% CI, 1.00-2.96; log-rank test, P = 0.047).ConclusionsTumor heterogeneity induced differences in identifying ICI subtypes of CRC patients. The ICI score may serve as an effective biomarker for predicting prognosis, help identify new therapeutic markers for CRC, and develop novel effective immune checkpoint blockade therapies.
| S-EPMC10089677 | biostudies-literature