HER-2 Expression in Colorectal Cancer and Its Correlation with Immune Cell Infiltration
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ABSTRACT:
SUBMITTER: Yang D
PROVIDER: S-EPMC10668975 | biostudies-literature | 2023 Oct
REPOSITORIES: biostudies-literature
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Project description:IntroductionColorectal cancer (CRC) is a prevalent malignancy with significant morbidity and mortality worldwide. A deeper understanding of the interaction of cancer cells with other cells in the tumor microenvironment is crucial to devise effective therapeutic strategies. MUC2, a major component of the protective mucus layer in the gastrointestinal tract, has been implicated in CRC progression and immune response regulation.MethodIn this study, we sought to elucidate the relationship between MUC2 expression and immune infiltration within CRC using in vitro models involving two well-established cell lines, HT-29 and LS-174T. By employing CRISPR-mediated MUC2 knockout, we investigated the influence of MUC2 on tumor immune infiltration and its interplay with T cells and NK cells enriched peripheral blood mononuclear cells (PBMCs) in 3D spheroid cultures.ResultsWhile MUC2 was more abundant in LS-174T cell line compared to HT-29, its knockout resulted in increased immune infiltration solely in the HT-29 cell line, but not in the LS-174T cell line. We revealed that the removal of MUC2 protein was compensated in LS-174T by the expression of other gel-forming mucin proteins (MUC6, MUC5B) commonly expressed in the gastrointestinal epithelium, while this was not observed in HT-29 cell line.ConclusionOur study is the first to demonstrate that MUC2 functions as a physical barrier to immune infiltration in colorectal cancer (CRC) in vitro. In HT-29 cells, MUC2 knockout increased immune infiltration, while in LS-174T cells, compensatory expression of other mucins (MUC6, MUC5B) maintained the barrier. These findings reveal the complexity of mucin biology in CRC and suggest that targeting mucin pathways could be a novel therapeutic approach.
| S-EPMC11802499 | biostudies-literature
Project description:BackgroundImmune checkpoint inhibitors (ICIs) have rapidly revolutionized colorectal cancer (CRC) treatment, but resistance caused by the heterogeneous tumor microenvironment (TME) still presents a challenge. Therefore, it is necessary to characterize TME immune infiltration and explore new targets to improve immunotherapy.MethodsThe compositions of 64 types of infiltrating immune cells and their relationships with CRC patient clinical characteristics were assessed. Differentially expressed genes (DEGs) between "hot" and "cold" tumors were used for functional analysis. A prediction model was constructed to explore the survival of CRC patients treated with and without immunotherapy. Finally, fatty acid-binding protein (FABP6) was selected for in vitro experiments, which revealed its roles in the proliferation, apoptosis, migration, and immunogenicity of CRC tissues and cell lines.ResultsThe infiltration levels of several immune cells were associated with CRC tumor stage and prognosis. Different cell types showed the synergistic or antagonism infiltration patterns. Enrichment analysis of DEGs revealed that immune-related signaling was significantly activated in hot tumors, while metabolic process pathways were altered in cold tumors. In addition, the constructed model effectively predicted the survival of CRC patients treated with and without immunotherapy. FABP6 knockdown did not significantly alter tumor cell proliferation, apoptosis, and migration. FABP6 was negatively correlated with immune infiltration, and knockdown of FABP6 increased major histocompatibility complex (MHC) class 1 expression and promoted immune-related chemokine secretion, indicating the immunogenicity enhancement of tumor cells. Finally, knockdown of FABP6 could promote the recruitment of CD8+ T cells.ConclusionCollectively, we described the landscape of immune infiltration in CRC and identified FABP6 as a potential immunotherapeutic target for treatment.
| S-EPMC9403257 | biostudies-literature
Project description:A substantial fraction of patients with stage I-III colorectal adenocarcinoma (CRC) experience disease relapse after surgery with curative intent. However, biomarkers for predicting the likelihood of CRC relapse have not been fully explored. Therefore, we assessed the association between tumor infiltration by a broad array of innate and adaptive immune cell types and CRC relapse risk. We implemented a discovery-validation design including a discovery dataset from Moffitt Cancer Center (MCC; Tampa, FL) and three independent validation datasets: (1) GSE41258 (2) the Molecular Epidemiology of Colorectal Cancer (MECC) study, and (3) GSE39582. Infiltration by 22 immune cell types was inferred from tumor gene expression data, and the association between immune infiltration by each cell type and relapse-free survival was assessed using Cox proportional hazards regression. Within each of the four independent cohorts, CD4+ memory activated T cell (HR: 0.93, 95% CI: 0.90-0.96; FDR = 0.0001) infiltration was associated with longer time to disease relapse, independent of stage, microsatellite instability, and adjuvant therapy. Based on our meta-analysis across the four datasets, 10 innate and adaptive immune cell types associated with disease relapse of which 2 were internally validated using multiplex immunofluorescence. Moreover, immune cell type infiltration was a better predictors of disease relapse than Consensus Molecular Subtype (CMS) and other expression-based biomarkers (Immune-AICMCC:238.1-238.9; CMS-AICMCC: 241.0). These data suggest that transcriptome-derived immune profiles are prognostic indicators of CRC relapse and quantification of both innate and adaptive immune cell types may serve as candidate biomarkers for predicting prognosis and guiding frequency and modality of disease surveillance.
| S-EPMC7951964 | biostudies-literature
Project description:SVIL is a member of the villin/gelsolin superfamily and is responsible for encoding supervillin. It has been reported to be closely related to the occurrence and development of various tumors. However, the mechanism of SVIL in bladder cancer has not been reported yet. In this research, we evaluated the relationship between SVIL expression and bladder cancer in public dataset and examined the expression of SVIL in bladder cancer cell lines, tissue microarrays and patients in our cohort. Our work determined that the expression of SVIL in bladder cancer tissue was significantly lower than that in normal tissue. However, in bladder cancer tissues, the high expression of SVIL is significantly associated with poor prognosis. This kind of duality is very novel and has great research value. The expression level of SVIL can well predict the survival time of bladder cancer patients, and is an independent risk factor of bladder cancer patients. The expression of SVIL is also closely related to the immune tumor microenvironment of bladder cancer. Our research provides a basis for personalized therapeutic targets for bladder cancer.
| S-EPMC10480233 | biostudies-literature
Project description:Abstract Background The 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. Methods The 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. Results The 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). Conclusions Tumor 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
Project description:Cancer-related immunity has been identified as playing a key role in the outcome of colorectal cancer (CRC); however, the exact mechanisms are only partially understood. In this study, we evaluated a total of 242 surgical specimen of CRC patients using tissue microarrays and immunohistochemistry to evaluate tumor infiltrating immune cells (CD3, CD4, CD8, CD20, CD23, CD45 and CD56) and immune checkpoint markers (CTLA-4, PD-L1, PD-1) in systematically selected tumor regions and their corresponding lymph nodes, as well as in liver metastases. Additionally, an immune panel gene expression assay was performed on 12 primary tumors and 12 consecutive liver metastases. A higher number of natural killer cells and more mature B cells along with PD-1+ expressing cells were observed in the main tumor area as compared to metastases. A higher number of metastatic lymph nodes were associated with significantly lower B cell counts. With more advanced lymph node metastatic status, higher leukocyte-particularly T cell numbers-were observed. Eleven differentially expressed immune-related genes were found between primary tumors and liver metastases. Also, alterations of the innate immune response and the tumor necrosis factor superfamily pathways had been identified.
| S-EPMC9024576 | biostudies-literature
Project description:BackgroundGalectin-9 is a member of the galectin family and has been reported to have a tumor-promoting or antitumor effect in response to the immune microenvironment. However, the immunomodulatory effect of galectin-9 in colorectal cancer (CRC) remains unclear. The antigen presentation and antitumor immune effects of galectin-9 in CRC were examined in this study.MethodsThe expression of galectin-9, dendritic cell markers (CD208 and CD1a), T-cell markers (CD3 and CD8) and mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) was assessed using immunohistochemistry in CRC samples. The correlation between galectin-9 and immune cells or immunomodulatory factors was also evaluated via multiple gene expression databases.ResultsThe level of galectin-9 was decreased in mismatch repair-proficient patients compared with mismatch repair-deficient patients (p = 0.0335). GSEA showed that the regulatory mechanism of galectin-9 in CRC was related to a variety of immune pathways. Galectin-9 expression was strongly correlated with immune cell infiltration and immunomodulators (all p < 0.0001). In the relationship between galectin-9 expression and the infiltration of DCs, there was a negative correlation in CD1a + immature DCs (R = -0.263, p = 0.042). A strong positive correlation was observed in CD208 + mature DCs (R = 0.391, p < 0.01). Patients with high galectin-9 expression also exhibited abundant CD8 + T-cell and CD3 + T-cell infiltration.ConclusionCollectively, our findings provide evidence that galectin-9 may increase the antitumor immune response of patients with CRC. DCs play an important role in galectin-9-mediated antitumor immune responses, which provides further insight into the development of immunotherapy.
| S-EPMC9756675 | biostudies-literature
Project description:Cetuximab has activity against colorectal cancers. Recent studies demonstrated that cetuximab induces antibody-dependent cell-mediated cytotoxicity via immune cells, and a new immune-related mechanism of inducing immunogenic cell death. This study aimed to evaluate the immune responses induced by cetuximab in tumor microenvironments at liver metastasis sites of metastatic colorectal cancer patients. We assessed immune cell infiltration in the liver metastatic sites of 53 colorectal cancer patients. These patients were divided into three groups according to the treatment before operation: chemotherapy with cetuximab, chemotherapy without cetuximab, and no chemotherapy. The inflammatory cells in the liver metastatic sites were assessed by hematoxylin-eosin staining, focusing on the invasive margin. The overall inflammatory reaction and number of lymphoid cells were assessed with a four-point scoring system. We then assessed immune cell infiltration (CD3, CD8 and CD56) in 15 liver metastatic sites. Hematoxylin-eosin staining demonstrated more inflammatory cells in the chemotherapy with cetuximab group than in the other groups (P < 0.001). Of note, inflammatory cells were found in intratumoral areas, and the destruction of cancer cell foci was observed in the chemotherapy with cetuximab group. Moreover, a higher infiltration of CD3+ (P = 0.003), CD8+ (P = 0.003) and CD56+ (P = 0.001) cells was observed in the chemotherapy with cetuximab group than in the other groups. These results suggest that cetuximab might have an immune-enhancing effect. As such, the immune-related mechanism of action of cetuximab may enhance the efficacy of combination therapy, such as chemotherapy and immunotherapy using therapeutic peptides.
| S-EPMC5378263 | biostudies-literature
Project description: Not available
| S-EPMC8101534 | biostudies-literature
Project description:To investigate the pathophysiological significance of infiltrating antitumour immune cells, we evaluated the quantity of immune cell intratumoral infiltration in 110 surgically resected gallbladder specimens by immunohistochemistry. We examined 45 cases of gallbladder cancer and 65 cases of benign gallbladder diseases for CD4(+) T cells, CD8(+) T cells, natural killer cells (NKCs), and dendritic cells (DCs). High levels of CD4(+) T cell, CD8(+) T cell, NKC, and DC infiltration were recognised in 51.1% (23 out of 45), 37.8% (17 out of 45), 33.3% (15 out of 45), and 48.9% (22 out of 45) of cancer specimens, respectively. High numbers of infiltrating CD4(+) and CD8(+) T cells correlated with decreasing tumour invasion, and high numbers of infiltrating DCs correlated with decreasing lymph-node tumour metastasis. Furthermore, increased infiltration of CD4(+) and CD8(+) T cells and DCs exhibited a significant correlation with prolonged survival. NKC infiltration, however, did not correlate with any of the clinicopathological factors examined. Additionally, high levels of infiltration were not identified in specimens from benign diseases, consistent with the cancer-specific activity of CD4(+) and CD8(+) T cells and DCs. In this study, we demonstrate that CD4(+) and CD8(+) tumour-infiltrating lymphocyte and DCs, but not NKCs, are important factors in the accurate prognosis of survival after surgical removal of gallbladder adenocarcinoma.
| S-EPMC2394404 | biostudies-other