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PPI network and modules for differentially expressed genes in tumor-infiltrating T cells between colon cancer and rectal cancer. PPI network shows the interactions for differentially expressed genes in tumor-infiltrating T cells between colon cancer and rectal cancer. Triangle nodes represent the up-regulated genes and V-shaped nodes represent the down-regulated genes; node size represent the degree of the node in network; red nodes represent genes in module 1 and blue nodes represent genes in module 2. C1, tumor-Treg; C2, CD4+ tissue-resident memory T cells; C3, CD4+ effector memory T cells; C5, CD8+ effector memory T cells; C7, CD8+ tissue-resident memory T cells.
Source publication
Objective
This study aimed to characterize the tumor-infiltrating T cells in moderately differentiated colorectal cancer.
Methods
Using single-cell RNA sequencing data of isolated 1632 T cells from tumor tissue and 1252 T cells from the peripheral blood of CRC patients, unsupervised clustering analysis was performed to identify functionally distin...
Citations
... These studies highlighted the heterogeneity in liver metastasis of CRC and enabled the identification and functional evaluation of T cell subsets in TIME [58]. In 2021, Yang et al. discovered eight T cell subsets through scRNA-seq-based analysis on T lymphocytes in CRC patient-derived tumor and peripheral blood samples, validating significant correlation between Th17 cells and tumorinfiltrating Tregs, as well as a positive correlation between CD8+IEL and CD8+TRM [59]. Wang et al. [60] analyzed the transcriptional differences of cell atlas between primary and liver metastatic CRC by single-cell RNA sequencing, and uncovered the dynamic nature of immune cells in different cancer settings (Figure 2). ...
Colorectal cancer (CRC) is a highly prevalent malignancy in the digestive system around the globe that is characterized by intricate pathogenesis, progression and poor prognosis. Recent studies indicate that tumor immune microenvironment (TIME) is a crucial mediator of tumorigenesis and progression with substantial diagnostic and prognostic value, which is a complex network of malignant cells, immune cells, endothelial cells, extracellular matrix, interstitial components and various molecular factors. Therefore, comprehensive profiling of CRC-associated TIME may substantially contribute to the research on CRC pathology while accelerating pharmaceutical development for effective CRC immunotherapy. However, CRC tissues tend to exhibit high cell heterogeneity, which severely compromises the accuracy of the TIME profiling data acquired through conventional sequencing methods as they are incapable of discriminating different cell populations. Single-cell sequencing (SCS) is a novel sequencing technology capable of comprehensively characterizating individual cells at a high resolution, thereby preserving heterogeneous tissue information and the transcriptional data of rare cell populations. SCS technology-enabled profiling of CRC-associated TIME offers emerging opportunities for elucidating the pathogenesis and progression mechanisms of CRC. This work provides a comprehensive summary on the unique merits and potential breakthroughs of SCS technology in the context of CRC-associated TIME characterization, which may facilitate the development and optimization of intervention strategies for CRC in the clinics.
... Varied tumor-infiltrating signatures have been observed for colon and rectal cancers studied separately, with the presence of CD8+ cells noted in rectal cancer and missing from colon cancer. However, CD8+ cells existed in the peripheral blood of colon cancer patients but lacked in rectal cancer [68]. ...
Colorectal cancer (CRC) originates from the polyps lining the colon and is among the most common types of cancer. With the increasing popularity of single-cell sequencing technologies, researchers have been able to better understand the immune landscape of colorectal cancer, by analyzing their expression and interactions in detail with the tumor microenvironment (TME) at single-cell level. Since the tumor-immune cell interactions play a critical part in the advancement as well as treatment response in colorectal cancer, the release of inhibitory factors such as T cells are important for recognizing and destroying cancer cells. Such information is vital to identify immunotherapeutic targets for cure and monitoring response to treatments. Therefore, a comprehensive single-cell studies-based overview of key immunogenic agents regulating the TME of CRC is provided in this review. Tumor-associated macrophages can promote tumor growth and resistance to treatment by releasing factors that inhibit the function of other immune cells. Additionally, colorectal cancer cells can express programmed cell death protein 1 and its ligand, which can also inhibit T-cell function. Researchers have found that certain types of immune cells, prominently T cells, natural killer, and dendritic cells, can have a positive impact on the prognosis of colorectal cancer patients. Treatments like immune checkpoint inhibitors and CAR-T therapies that help to release the inhibitory signals from the cancer cells allow the immune cells to function more effectively.
... High cholesterol can lead to the immune escape of cancer cells by inducing CD8 + T cell exhaustion. In previous studies, through genomic big data analysis and in vivo and in vitro experimental studies, we have indeed found that high cholesterol can induce exhaustion of CD8 + T cells and lead to immune escape from CRC [27,28]. What is the specific mechanism by which cholesterol induces exhaustion of CD8 + T cells in CRC? ...
Hypercholesterolemia is one of the risk factors for colorectal cancer (CRC). Cholesterol can participate in the regulation of human T cell function and affect the occurrence and development of CRC.
To elucidate the pathogenesis of CRC immune escape mediated by CD8+ T cell exhaustion induced by cholesterol.
CRC samples (n = 217) and healthy individuals (n = 98) were recruited to analyze the relationship between peripheral blood cholesterol levels and the clinical features of CRC. An animal model of CRC with hypercholesterolemia was established. Intraperitoneal intervention with endoplasmic reticulum stress (ERS) inhibitors in hypercholesterolemic CRC mice was performed. CD69, PD1, TIM-3, and CTLA-4 on CD8+ T cells of spleens from C57BL/6 J mice were detected by flow cytometry. CD8+ T cells were cocultured with MC38 cells (mouse colon cancer cell line). The proliferation, apoptosis, migration and invasive ability of MC38 cells were detected by CCK-8 assay, Annexin-V APC/7-AAD double staining, scratch assay and transwell assay, respectively. Transmission electron microscopy was used to observe the ER structure of CD8+ T cells. Western blotting was used to detect the expression of ERS and mitophagy-related proteins. Mitochondrial function and energy metabolism were measured. Immunoprecipitation was used to detect the interaction of endoplasmic reticulum-mitochondria contact site (ERMC) proteins. Immunofluorescence colocalization was used to detect the expression and intracellular localization of ERMC-related molecules.
Peripheral blood cholesterol-related indices, including Tc, low density lipoproteins (LDL) and Apo(a), were all increased, and high density lipoprotein (HDL) was decreased in CRCs. The proliferation, migration and invasion abilities of MC38 cells were enhanced, and the proportion of tumor cell apoptosis was decreased in the high cholesterol group. The expression of IL-2 and TNF-α was decreased, while IFN-γ was increased in the high cholesterol group. It indicated high cholesterol could induce exhaustion of CD8+ T cells, leading to CRC immune escape. Hypercholesterolemia damaged the ER structure of CD8+ T cells and increased the expression of ER stress molecules (CHOP and GRP78), lead to CD8+ T cell exhaustion. The expression of mitophagy-related proteins (BNIP3, PINK and Parkin) in exhausted CD8+ T cells increased at high cholesterol levels, causing mitochondrial energy disturbance. High cholesterol enhanced the colocalization of Fis1/Bap31, MFN2/cox4/HSP90B1, VAPB/PTPIP51, VDAC1/IPR3/GRP75 in ERMCs, indicated that high cholesterol promoted the intermolecular interaction between ER and mitochondrial membranes in CD8+ T cells.
High cholesterol regulated the ERS-ERMC-mitophagy axis to induce the exhaustion of CD8+ T cells in CRC.
... Rayrf et al. [31] found that neutrophil polarization was lost in liver metastasis of colon cancer mice with induced liver-specific IGF-I deficiency. Literature [32] revealed that T cells CD8 of colon and rectal cancer showed changes in gene expression patterns. ...
Colon carcinoma is a highly malignant tumor, its early symptoms are not obvious, and its prognosis is poor. Therefore, it is urgent to develop more prognostic markers of colon cancer. Many long non-coding RNAs (lncRNAs) have been proven to play an active role in tumor diagnosis, prognosis, and immunotherapy. On the other hand, the crucial role of immunogenic cell death (ICD) is in tumor inhibition. This paper aims to integrate ICD-related genes with lncRNAs and explore the mechanism of action of ICD-related lncRNAs in colon cancer. Therefore, this paper proposes a multi-constraint canonical correlation analysis to explore ICD-related lncRNAs. Furthermore, this paper uses univariate and Lasso-Cox regression to construct and verify the prognosis model of the top important lncRNAs. In this paper, according to the model's risk score, colon cancer samples are divided into a high-risk group and a low-risk group, and the effect of the model is verified based on the TCGA queue and GEO queue, respectively. In addition, we analyzed the similarities and differences in functional enrichment, immune infiltration, and drug sensitivity between the two risk groups in detail. There was a significant difference in the infiltrating abundance of T cells CD8 between high- and low-risk groups. Therefore, this article re-clusters T cell clusters based on single-cell sequencing (scRNA-seq) data of colon cancer. The unique pathways involved in the genes of the CD8 subpopulation of T cells and their communication with other T cell subpopulations were explored. In summary, the ICD-related lncRNAs risk model determined in this paper can provide a reference for predicting colon cancer patients' prognosis and drug sensitivity.
... [24] Pharmacological analgesia, as the main modality for the treatment of colorectal cancer pain, has formed a 3-step analgesic treatment principle. [25][26][27][28] However, a large number of studies have found that the therapeutic effect of long-term analgesic drugs is not ideal, and the incidence of adverse reactions in patients after treatment is relatively high, which not only affects the clinical treatment but also has a great impact on the quality of life of patients. [29] The use of mind mapping in the health education of cancer patients to evaluate the level of pain, medication compliance, and patient satisfaction has enabled patients to control their pain and acquire knowledge about medication after the intervention. ...
Mind mapping is a combination of images and logical thinking in the form of pictures and texts. It presents a natural expression process that conforms to the divergent thinking of the brain, helping patients understand memory. This study aimed to investigate the impact of pain-education nursing with the aid of mind maps on postoperative pain scores and quality of life in patients with colorectal cancer. The medical records of 100 colorectal cancer patients treated from July 2020 to July 2022 were selected as retrospective research participants and divided into control and observation groups. The control group received routine pain care, and the observation group was given pain-education nursing based on a mind map. The effects on quality of life, pain, negative emotions, and comfort after nursing were compared between the 2 groups. There was no significant difference in quality of-life scores between the 2 groups before the nursing intervention (P > .05). After nursing, the physical, emotional, cognitive, and social functions of patients in the observation group were significantly higher than those in the control group. However, the overall quality of life and financial difficulties of patients in the observation group were significantly lower than those in the control group (P < .05). The observation group's social, physical, and psychological comfort scores were significantly higher than those in the control group after nursing intervention (P < .05). After nursing, the observation group's visual analog scale scores at different times after the operation were significantly lower than those of the control group. The scores on the self-rating anxiety scale and self-rating depression scale in the observation group were significantly lower than those in the control group (P < .05). Pain-education nursing based on mind maps can effectively improve the daily living ability, pain symptoms, and quality of life of patients after colorectal cancer, and there is a reference value for post-nursing care of patients after colorectal cancer.
... Rayrf et al. [31] discovered that neutrophil polarisation was lost in colon cancer mice with induced liver-specific IGF-I deficiency during liver metastasis. According to the literature [32], T cells CD8 from colon and rectal cancer showed changes in gene expression patterns. ...
The prognosis for colon carcinoma is poor, it is a highly aggressive tumor, and its early symptoms are subtle. Hence, the need for more colon cancer prognostic indicators is urgent. Many long non-coding RNAs (lncRNAs) are known to actively contribute to the detection, prognosis, and treatment of tumors. On the other hand, immunogenic cell death (ICD) is vital for the prevention of tumors. This study seeks to research the mechanism of action of ICD-related lncRNAs in colon cancer and integrate ICD-related genes with lncRNAs. In order to investigate ICD-related lncRNAs, this research suggests a multi-constraint canonical correlation analysis. The prognostic model of the most significant lncRNAs is also constructed and verified in this paper using univariate and Lasso-Cox regression. In this study, colon cancer samples are split into high-risk and low-risk groups based on the model's risk score, and the impact of the model is assessed using the TCGA queue and the GEO queue, respectively. Also, we thoroughly examined the parallels and discrepancies in immune infiltration, functional enrichment, and medication sensitivity across the two risk groups. In conclusion, the ICD-related lncRNAs risk model developed in this research can serve as a guide for predicting the prognosis and therapeutic sensitivity of colon cancer patients.
... However, the function of TILs can be controlled and inhibited by Treg cells [207]. Using the clustering analysis, Yang et al. identified eight T cell types from tumor tissues, including tumor Tregs, CD4+/CD8+ TRM T cells, CD4+/CD8+ effector memory T cells, Th17 cells, depleted CD8+ T cells, and CD8+ intraepithelial lymphocytes [208]. These T cell types likely represent the predominant tumor-infiltrating T cell subset in moderately differentiated CRC [208]. ...
... Using the clustering analysis, Yang et al. identified eight T cell types from tumor tissues, including tumor Tregs, CD4+/CD8+ TRM T cells, CD4+/CD8+ effector memory T cells, Th17 cells, depleted CD8+ T cells, and CD8+ intraepithelial lymphocytes [208]. These T cell types likely represent the predominant tumor-infiltrating T cell subset in moderately differentiated CRC [208]. Treg cells in human colon tumor tissues express immunosuppressive molecules such as PD-1, cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), T cell immunoglobulin and mucin domain-3 (TIM-3) and lymphocyte-activation gene 3 (LAG-3) [209]. ...
The study of the tumor microenvironment (TME) has become an important part of colorectal cancer (CRC) research. Indeed, it is now accepted that the invasive character of a primary CRC is determined not only by the genotype of the tumor cells, but also by their interactions with the extracellular environment, which thereby orchestrates the development of the tumor. In fact, the TME cells are a double-edged sword as they play both pro-and anti-tumor roles. The interaction of the tumor-infiltrating cells (TIC) with the cancer cells induces the polarization of the TIC, exhibiting an antagonist phenotype. This polarization is controlled by a plethora of interconnected pro-and anti-oncogenic signaling pathways. The complexity of this interaction and the dual function of these different actors contribute to the failure of CRC control. Thus, a better understanding of such mechanisms is of great interest and provides new opportunities for the development of personalized and efficient therapies for CRC. In this review, we summarize the signaling pathways linked to CRC and their implication in the development or inhibition of the tumor initiation and progression. In the second part, we enlist the major components of the TME and discuss the complexity of their cells functions.
... Deciphering the precise cellular composition and developmental trajectory of COAD has helped identify novel genes associated with pathogenesis and underlying mechanisms for the malignant transformation of COAD (4). Moreover, the single-cell sequencing technology has allowed us to explore the immune microenvironment of COAD, which will aid in identifying potential targets for immunotherapy for the treatment of COAD (5). ...
Background
Colon adenocarcinoma (COAD) is a fatal disease, and its cases are constantly increasing worldwide. Further, the therapeutic and management strategies for patients with COAD are still unsatisfactory due to the lack of accurate patient classification and prognostic models. Therefore, our study aims to identify prognostic markers in patients with COAD and construct a cell subtype-specific prognostic model with high accuracy and robustness.
Methods
Single-cell transcriptomic data of six samples were retrieved from the Gene expression omnibus (GEO) database. The cluster annotation and cell-cell communication analysis identified enterocytes as a key player mediating signal communication networks. A four-gene signature prognostic model was constructed based on the enterocyte-related differentially expressed genes (ERDEGs) in patients with COAD of the Cancer Genome Atlas cohort. The prognostic model was validated on three external validation cohorts from the GEO database. The correlation between immune cell infiltration, immunotherapy response, drug sensitivity, and the four-gene signature prognostic model was investigated. Finally, immunohistochemistry (IHC) was performed to determine the expression of the four genes.
Results
We found that the proportion of epithelial cells was obviously large in COAD samples. Further analysis of epithelial cells showed that the activity of the enterocytes was highest in the cell-cell communication network. Based on enterocyte data, 30 ERDEGs were identified and a 4-gene prognostic model including CPM, CLCA4, ELOVL6, and ATP2A3 was developed and validated. The risk score derived from this model was considered as an independent variable factor to predict overall survival. The patients were divided into high- and low-risk groups based on the median riskscore value. The correlation between immune cell infiltration, immunotherapy response, immune status, clinical characteristics, drug sensitivity, and risk score was analyzed. IHC confirmed the expression of signature genes in tissues from normal individuals, patients with polyps, and COAD.
Conclusion
In this study, we constructed and validated a novel four-gene signature prognostic model, which could effectively predict the response to immunotherapy and overall survival in patients with COAD. More importantly, this model provides useful insight into the management of colon cancer patients and aids in designing personalized therapy.
... Probing TIME and cellular heterogeneity contributes significantly to cancer immunotherapy. Scientists revealed functionally distinct T cell composition patterns by scRNA-seq in colorectal cancer (CRC) and patients' peripheral blood [93]. Based on cell characteristics and gene expression levels, the differences in the composition of tumor-infiltrating T cell populations in colon cancer and rectal cancer were demonstrated. ...
Recently, immunotherapy has gained increasing popularity in oncology. Several immunotherapies obtained remarkable clinical effects, but the efficacy varied, and only subsets of cancer patients benefited. Breaking the constraints and improving immunotherapy efficacy is extremely important in precision medicine. Whereas traditional sequencing approaches mask the characteristics of individual cells, single-cell sequencing provides multiple dimensions of cellular characterization at the single-cell level, including genomic, transcriptomic, epigenomic, proteomic, and multi-omics. Hence, the complexity of the tumor microenvironment, the universality of tumor heterogeneity, cell composition and cell–cell interactions, cell lineage tracking, and tumor drug resistance mechanisms are revealed in-depth. However, the clinical transformation of single-cell technology is not to the point of in-depth study, especially in the application of immunotherapy. The newly discovered vital cells and tremendous biomarkers facilitate the development of more efficient individualized therapeutic regimens to guide clinical treatment and predict prognosis. This review provided an overview of the progress in distinct single-cell sequencing methods and emerging strategies. For perspective, the expanding utility of combining single-cell sequencing and other technologies was discussed.
... The colorectal tumor immune microenvironment (TIME) is a heterogeneous microenvironment containing a variety of immune cells and their products in tumor tissues (44). Many scRNA-seq studies have found a link between significant infiltration of CD8 + T cells (45), CD4 + T helper 1 (Th1) (46), regulatory T (Treg) cells (47), tumor-infiltrating exhausted T cells (48), CD45 + macrophages, dendritic cells, and myeloid cells (49), and a favourable outcome in mCRC. However, these immune cells, particularly T cells are always in a hyporesponsive state, a phenomenon often referred to as exhaustion (30). ...
Single cell RNA sequencing (scRNA-seq) is a novel high-throughput technique that enables the investigation of a single cell’s entire transcriptome. It elucidates intricate cellular networks and generates indices that will eventually enable the development of more targeted and personalized medications. The importance of scRNA-seq has been highlighted in complex biological systems such as cancer and the immune system, which exhibit significant cellular heterogeneity. Colorectal cancer (CRC) is the third most common type of cancer and the second leading cause of cancer-related death globally. Chemotherapy continues to be used to treat these patients. However, 5-FU has been utilized in chemotherapy regimens with oxaliplatin and irinotecan since the 1960s and is still used today. Additionally, chemotherapy-resistant metastatic CRCs with poor prognoses have been treated with immunotherapy employing monoclonal antibodies, immune checkpoint inhibitors, adoptive cell therapy and cancer vaccines. Personalized immunotherapy employing tumor-specific neoantigens allows for treating each patient as a distinct group. Sequencing and multi-omics approaches have helped us identify patients more precisely in the last decade. The introduction of modern methods and neoantigen-based immunotherapy may usher in a new era in treating CRC. The unmet goal is to better understand the cellular and molecular mechanisms that contribute to CRC pathogenesis and resistance to treatment, identify novel therapeutic targets, and make more stratified and informed treatment decisions using single cell approaches. This review summarizes current scRNA-seq utilization in CRC research, examining its potential utility in the development of precision immunotherapy for CRC.
