scholarly journals TNFRSF11B Suppresses Memory CD4+ T Cell Infiltration in the Colon Cancer Microenvironment: A Multiomics Integrative Analysis

2021 ◽  
Vol 12 ◽  
Author(s):  
Jun-rong Zhang ◽  
Ping Hou ◽  
Xiao-jie Wang ◽  
Zong-qi Weng ◽  
Xin-chang Shang-guan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
T Cells ◽  
Lymph Node ◽  
Cancer Patients ◽  
Cd4 T Cell ◽  
Cancer Microenvironment ◽  
Facs Analysis ◽  
E Coli ◽  
T Cell Infiltration

BackgroundColorectal cancer is a lethal cancer worldwide. Due to the low tumor mutation burden and low proportion of tumor-infiltrating lymphocytes in the microenvironment of most patients, innovative immunotherapeutic approaches need to be identified.MethodsUsing the TCGA-COAD dataset (n = 514), we identified TNFRSF11B as a prognostic factor of colon cancer. An immunohistochemistry (IHC) dataset (n = 86), 290 single colorectal cancer cells (GSE81861), and 31 paired colon cancer transcriptional datasets were further applied to validate the function of TNFRSF11B, which was confirmed via fluorescence-activated cell sorting (FACS) analysis.ResultsA risk score system consisting of eight immune-related genes (IRGs) (FGFR2, ZC3HAV1L, TNFRSF11B, CD79A, IGHV3-11, IGHV3-21, IGKV2D-30, and IGKV6D-21) was constructed to predict the prognosis of colon cancer patients. Only TNFRSF11B was closely correlated with late-stage lymph node metastasis and worse survival outcomes (p = 0.010, p = 0.014, and p = 0.0061). In our IHC dataset, 72.09% (62/86) of the colon cancer patients had TNFRSF11B overexpression with significantly shorter overall survival times (p = 0.072). High TNFRSF11B expression typically had a later TNM stage (p = 0.067), a higher frequency of lymph node (p = 0.029) and lymphovascular (p = 0.007) invasion, and a higher incidence of pneumonia (p = 0.056) than their counterparts. The expression of six genes (KRT18, ARPC5L, ACTG1, ARPC2, EZR, and YWHAZ) related to pathogenic E. coli infection was simultaneously increased with TNFRSF11B overexpression via gene set enrichment analysis (GSEA). These genes are involved in the regulation of the actin cytoskeleton, shigellosis, bacterial invasion of epithelial cells, and Salmonella infection. Finally, only activated memory CD4+ T cells (p = 0.017) were significantly decreased in the high TNFRSF11B expression group via CIBERSORT comparison, which was confirmed by TIMER2.0 analysis of the TCGA-COAD dataset. We also performed FACS analysis to show that TNFRSF11B decreased the infiltration of central memory CD4+ T cells and effector memory CD4+ T cells in the colorectal cancer microenvironment (all p <0.001).ConclusionTNFRSF11B acts as a prognostic factor for colon cancer patients and could affect the colon cancer immune response. TNFRSF11B was closely related to lymph node invasion and pathogenic E. coli. infection, which may negatively affect memory-activated CD4+ T cell infiltration in colon cancer.

scholarly journals Clinicopathological Factors Influencing Lymph Node Yield in Colorectal Cancer: A Retrospective Study

2019 ◽  
Vol 2019 ◽  
pp. 1-6 ◽  
Author(s):  
Elena Orsenigo ◽  
Giulia Gasparini ◽  
Michele Carlucci
Keyword(s):  
Colorectal Cancer ◽  
Rectal Cancer ◽  
Colon Cancer ◽  
Lymph Node ◽  
Lymph Nodes ◽  
Cancer Patients ◽  
Rank Test ◽  
Lymph Node Yield ◽  
Log Rank Test ◽  
Lymph Node Retrieval

Many colorectal resections do not meet the minimum of 12 lymph nodes (LNs) recommended by the American Joint Committee on Cancer for accurate staging of colorectal cancer. The aim of this study was to investigate factors affecting the number of the adequate nodal yield in colorectal specimens subject to routine pathological assessment. We have retrospectively analysed the data of 2319 curatively resected colorectal cancer patients in San Raffaele Scientific Institute, Milan, between 1993 and 2017 (1259 colon cancer patients and 675 rectal cancer patients plus 385 rectal cancer patients who underwent neoadjuvant therapy). The factors influencing lymph node retrieval were subjected to uni- and multivariate analyses. Moreover, a survival analysis was carried out to verify the prognostic implications of nodal counts. The mean number of evaluated nodes was 24.08±11.4, 20.34±11.8, and 15.33±9.64 in surgically treated right-sided colon cancer, left-sided colon cancer, and rectal tumors, respectively. More than 12 lymph nodes were reported in surgical specimens in 1094 (86.9%) cases in the colon cohort and in 425 (63%) cases in the rectal cohort, and patients who underwent neoadjuvant chemoradiation were analysed separately. On univariate analysis of the colon cancer group, higher LNs counts were associated with female sex, right colon cancer, emergency surgery, pT3-T4 diseases, higher tumor size, and resected specimen length. On multivariate analysis right colon tumors, larger mean size of tumor, length of specimen, pT3-T4 disease, and female sex were found to significantly affect lymph node retrieval. Colon cancer patients with 12 or more lymph nodes removed had a significantly better long-term survival than those with 11 or fewer nodes (P=0.002, log-rank test). Rectal cancer patients with 12 or more lymph nodes removed approached but did not reach a statistically different survival (P=0.055, log-rank test). Multiple tumor and patients’ factors are associated with lymph node yield, but only the removal of at least 12 lymph nodes will reliably determine lymph node status.

Clinical lymph node staging by imaging in colorectal cancer: A flip of the coin?

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15160-e15160 ◽  
Author(s):  
Nelleke Pietronella Maria Brouwer ◽  
Rutger Carel Hubert Stijns ◽  
Lemmens Valery ◽  
Iris D. Nagtegaal ◽  
Regina GH Beets-Tan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Rectal Cancer ◽  
Colon Cancer ◽  
Lymph Node ◽  
Lymph Nodes ◽  
Neoadjuvant Therapy ◽  
Cancer Patients ◽  
Lymph Node Staging ◽  
Preoperative Treatment ◽  
Positive Lymph Nodes

e15160 Background: Clinical lymph node staging by MRI and CT is important in stratification for neoadjuvant therapy in colorectal cancer. Overstaging may result in unnecessary neoadjuvant therapy, but understaging may refrain patients from adequate preoperative treatment. This study aims to provide insight in current daily practice in clinical lymph node staging in CRC in the Netherlands. Methods: All patients with primary CRC, diagnosed between 2003-2014, who underwent lymph node dissection were selected from the nationwide population-based Netherlands Cancer Registry (n=100,211). Trends in patient- and tumor-characteristics, and lymph node staging were analyzed. For the years 2011-2014, sensitivity, specificity, positive (PPV) and negative predictive value (NPV) were calculated for clinical lymph node staging, with histology as the gold standard. Only patients without preoperative treatment were analyzed. Since prospective studies have shown that 5x5 Gy radiotherapy (RT) followed by total mesorectal excision within 10 days does not lead to nodal downstaging, an additional analysis was performed in this group. Results: The proportion clinically positive lymph nodes increased significantly between 2003-2014; from 7% to 22% for colon cancer and from 7% to 53% for rectal cancer. The proportion histological positive lymph nodes remained fairly stable over time (±35% colon, ±33% rectum). During 2011-2014, clinical lymph node staging was available in the registry in 86% of colon cancer patients, 92% of rectal cancer patients without neoadjuvant treatment and 95% of rectal cancer patients with 5x5 Gy RT. The parameters based on data from this period are presented in table 1. Conclusions: With a sensitivity and PPV of approximately 50%, clinical lymph node staging is about as accurate as flipping a coin. This leads to overtreatment in patients with rectal cancer with neoadjuvant RT. Acceptable specificity and NPV limit the risk of undertreatment. [Table: see text]

scholarly journals Cyst(e)ine in nutrition formulation promotes colon cancer growth and chemoresistance by activating mTORC1 and scavenging ROS

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Jiao Wu ◽  
Sai-Ching Jim Yeung ◽  
Sicheng Liu ◽  
Aiham Qdaisat ◽  
Dewei Jiang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Weight Loss ◽  
Cancer Patients ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Colorectal Cancer Patient ◽  
Nutrition Support ◽  
Immunodeficient Mice ◽  
The Impact

AbstractWeight loss and cachexia are common problems in colorectal cancer patients; thus, parenteral and enteral nutrition support play important roles in cancer care. However, the impact of nonessential amino acid components of nutritional intake on cancer progression has not been fully studied. In this study, we discovered that gastrointestinal cancer patients who received cysteine as part of the parenteral nutrition had shorter overall survival (P < 0.001) than those who did not. Cystine indeed robustly promotes colon cancer cell growth in vitro and in immunodeficient mice, predominately by inhibiting SESN2 transcription via the GCN2-ATF4 axis, resulting in mTORC1 activation. mTORC1 inhibitors Rapamycin and Everolimus block cystine-induced cancer cell proliferation. In addition, cystine confers resistance to oxaliplatin and irinotecan chemotherapy by quenching chemotherapy-induced reactive oxygen species via synthesizing glutathione. We demonstrated that dietary deprivation of cystine suppressed colon cancer xenograft growth without weight loss in mice and boosted the antitumor effect of oxaliplatin. These findings indicate that cyst(e)ine, as part of supplemental nutrition, plays an important role in colorectal cancer and manipulation of cyst(e)ine content in nutritional formulations may optimize colorectal cancer patient survival.

Behavior of Circulating CD4+CD25+Foxp3+ Regulatory T Cells in Colon Cancer Patients Undergoing Surgery

2011 ◽  
Vol 31 (6) ◽  
pp. 1095-1104 ◽  
Author(s):  
Ausilia Sellitto ◽  
Gennaro Galizia ◽  
Umberto De Fanis ◽  
Eva Lieto ◽  
Anna Zamboli ◽  
...  
Keyword(s):  
Colon Cancer ◽  
T Cells ◽  
Regulatory T Cells ◽  
Cancer Patients

Comparing of pan-cancer tumor immune microenvironment.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15100-e15100
Author(s):  
Jiaan Ye ◽  
Longgang Cui ◽  
Xiaochen Zhao ◽  
Guanghui Lan
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Natural Killer Cell ◽  
Natural Killer ◽  
Cancer Patients ◽  
Killer Cell ◽  
Immune Microenvironment ◽  
Hepatobiliary Cancer ◽  
Tumor Immune Microenvironment ◽  
Pan Cancer

e15100 Background: Cancer treatment has entered the era of immune checkpoint inhibitors (ICI), but different tumors have different responses to ICI drugs. For example, non-small cell lung cancer and melanoma have higher response rates to ICIs than colorectal cancer and liver cancer patients. Previous studies have shown that tumor immune microenvironment have a great impact on the efficacy of ICI. Methods: This study retrospectively included pan-cancer patient specimens, using multiple fluorescent labeling immunohistochemistry to explore the differences in the immune microenvironment of different tumors. Shapiro-Wilk was used for normality test, and ANOVA or Kruskal Wallis test was used according to the results. Two-sided P < 0.05 was considered a significant difference. Results: The study included 308 patients, including 119 (38.6%) NSCLC patients, 72 (23.4%) Colorectal cancer patients, 51 (16.6%) Hepatobiliary cancer patients and 66 (21.4%) Others types of cancer patients. Among them, there was 192 (62.3%) Male, and 116 (37.7%) Female, and the median age was 57 (50-66). The proportion of CD8+ T cells and natural killer cell in tumor was statistically different. The proportion of CD8+ T cells in NSCLC, Colorectal cancer, Hepatobiliary cancer and others was 2.16%, 1%, 1.77% and 2.63%, p < 0.01; the proportion of natural killer cell was 16.44 %, 4.91%, 5.58% and 3.29%, p < 0.01. Conclusions: Different tumor types have different immune microenvironments. These results may provide valuable clues for future ICI trail design.

Prognostic Characteristics of Colorectal Cancer Patients With Benign Mesenteric Lymph Node Enlargement

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Xianghui Huang ◽  
Yichen Yang ◽  
Qibing Liu ◽  
Xiaolong Tang ◽  
Jingbo Shi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lymph Node ◽  
Cancer Patients ◽  
Mesenteric Lymph Node ◽  
Mesenteric Lymph ◽  
Lymph Node Enlargement ◽  
Colorectal Cancer Patients

Novel CoupledCAR technology for treating colorectal cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2528-2528
Author(s):  
Lei Xiao ◽  
Song Li ◽  
Chengfei Pu ◽  
Zhiyuan Cao ◽  
Xinyi Yang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Complete Remission ◽  
Cancer Patients ◽  
Solid Tumors ◽  
Tumor Tissue ◽  
Lentiviral Vectors ◽  
Safety And Efficacy ◽  
Pet Ct ◽  
Colorectal Cancer Patients

2528 Background: Chimeric antigen receptor (CAR) T cell therapy has made significant progress in the treatment of blood cancers such as leukemia, lymphoma, and myeloma. However, the therapy faces many challenges in treating solid tumors. These challenges include physical barriers, tumor microenvironment immunosuppression, tumor heterogeneity, target specificity, and limited expansion in vivo. Methods: We designed a CAR lentivirus vector that consisted of a humanized CD19-specific single-chain variable fragment (scFv), a 4-1BB costimulatory domain, and a CD3ζ signaling domain.The lentivirus was produced by transfecting HEK-293T cells with CAR lentiviral vectors and viral packaging plasmids. Patient’s CD3 T cells was cultured in X-VIVO medium containing 125U/mL 1interleukin-2 (IL-2), and transduced with CAR lentivirus at certain MOI 24h after stimulated by anti-CD3/CD28 magnetic beads. Transduction efficiency was evaluated at 7 to 9 days after CAR lentivirus transduction, and quality controls for fungi, bacteria, mycoplasma, chlamydia, and endotoxin were performed. After infusion, serial peripheral blood samples were collected, and the expansion and the cytokine release of CART cells were detected by FACS and QPCR,respectively. The evaluation of response level for patients were performed at month 1,month 3,and month 6 by PET/CT. Results: We engineered CoupledCAR T cells with lentiviral vectors encoding an anti-GCC (guanylate cyclase 2C) CAR molecule. To verify the safety and efficacy of CoupledCAR-T cells for treating solid tumors, we conducted several clinical trials for different solid tumors, including seven patients with colorectal cancer. These seven patients failed multiple rounds of chemotherapy and radiotherapy. In the clinical trial, the metastatic colorectal cancer patients were infused with autologous anti-GCC CoupledCAR-T cells range from 4.9×105/kg to 2.9×106/kg. We observed that CoupledCAR-T cells expanded significantly in the patients and infiltrated tumor tissue sites, demonstrating enhanced anti-tumor activities. PET/CT showed significant tumor shrinkage and SUV max declined, and the ongoing responses were monitored. Patient 3 achieved complete response and the best overall response rate (ORR, include complete remission, complete metabolic response, and partial response.) was 57.1% (4/7), complete remission (CR) rate was 14.3% (1/7). Conclusions: In conclusion, the clinical data demonstrated that CoupledCAR-T cells effectively expanded, infiltrated tumor tissue sites, and kill tumor cells in patients with colorectal cancer. We used immunotherapy to achieve complete remission in patients with advanced colorectal cancer for the first time. We are recruiting more colorectal cancer patients to further test the safety and efficacy of anti-GCC CoupledCAR T cells. Since our CoupledCAR technology is a platform technology, we are expanding it to treat other solid tumors using different target tumor markers.

scholarly journals Biology of Nodal Spread in Colon Cancer: Insights from Molecular and Genetic Studies

2018 ◽  
Vol 59 (5-6) ◽  
pp. 361-370 ◽  
Author(s):  
Pridvi Kandagatla ◽  
Lilias H. Maguire ◽  
Karin M. Hardiman
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Molecular Markers ◽  
Lymph Node ◽  
Genetic Heterogeneity ◽  
Genetic Studies ◽  
Potential Models ◽  
Node Metastasis ◽  
Node Metastases ◽  
Nodal Spread

Colorectal cancer (CRC) lymph node metastases are common but their genetics and the mechanism whereby these metastases occur are not well understood. Here we present recent data regarding genetic heterogeneity in primary CRCs and their metastasis. In addition, we explain the different potential models describing the mechanisms of metastasis and the data supporting them. Multiple studies have also revealed a variety of prognostic molecular markers that are associated with lymph node metastasis in CRC. A better understanding of genetic heterogeneity and the mechanisms of metastasis is critical to predicting clinical response and resistance to targeted therapy.

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