scholarly journals Distinct Hypoxia-Related Gene Profiling Characterizes Clinicopathological Features and Immune Status of Mismatch Repair-Deficient Colon Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Yixin Xu ◽  
Junjie Hu ◽  
Can Cao ◽  
Mili Zhang ◽  
Youdong Liu ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Mismatch Repair ◽  
Immune Checkpoint ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Tumor Infiltrating Lymphocytes ◽  
Gene Signature ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
Gene Profiling

Despite dramatic responses to immune checkpoint inhibitors (ICIs) in patients with colon cancer (CC) harboring deficient mismatch repair (dMMR), more than half of these patients ultimately progress and experience primary or secondary drug resistance. There is no useful biomarker that is currently validated to accurately predict this resistance or stratify patients who may benefit from ICI-based immunotherapy. As hypoxic and acidic tumor microenvironment would greatly impair tumor-suppressing functions of tumor-infiltrating lymphocytes (TILs), we sought to explore distinct immunological phenotypes by analysis of the intratumoral hypoxia state using a well-established gene signature. Based on the Gene Expression Omnibus (GEO) (n = 88) and The Cancer Genome Atlas (TCGA) (n = 49) databases of patients with CC, we found that dMMR CC patients could be separated into normoxia subgroup (NS) and hypoxia subgroup (HS) with different levels of expression of hypoxia-related genes (lower in NS group and higher in HS group) using NMF package. Tumoral parenchyma in the HS group had a relatively lower level of immune cell infiltration, particularly CD8+ T cells and M1 macrophages than the NS group, and coincided with higher expression of immune checkpoint molecules and C-X-C motif chemokines, which might be associated with ICI resistance and prognosis. Furthermore, three genes, namely, MT1E, MT2A, and MAFF, were identified to be differentially expressed between NS and HS groups in both GEO and TCGA cohorts. Based on these genes, a prognostic model with stable and valuable predicting ability has been built for clinical application. In conclusion, the varying tumor-immune microenvironment (TIME) classified by hypoxia-related genes might be closely associated with different therapeutic responses of ICIs and prognosis of dMMR CC patients.

scholarly journals BRAF Mutation as a Potential Therapeutic Target for Checkpoint Inhibitors: A Comprehensive Analysis of Immune Microenvironment in BRAF Mutated Colon Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Shuyi Cen ◽  
Kun Liu ◽  
Yu Zheng ◽  
Jianzhen Shan ◽  
Chao Jing ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Braf Mutation ◽  
Plasma Cells ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Treatment Strategies ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
Immune Microenvironment ◽  
Tissue Specimens

BRAF mutated colon cancer presents with poor survival, and the treatment strategies are controversial. The tumor microenvironment, which plays a key role in tumorigenesis as well as responses to treatments, of this subtype is largely unknown. In the present study, we analyzed the differences of immune microenvironments between BRAF mutated and BRAF wild-type colon cancer utilizing datasets from The Cancer Genome Atlas and Gene Expression Omnibus and confirmed the findings by tissue specimens of patients. We found that BRAF mutated colon cancer had more stromal cells, more immune cell infiltration, and lower tumor purity. Many immunotherapeutic targets, including PD-1, PD-L1, CTLA-4, LAG-3, and TIM-3, were highly expressed in BRAF mutated patients. BRAF mutation was also correlated with higher proportions of neutrophils and macrophages M1, and lower proportions of plasma cells, dendritic cells resting, and T cells CD4 naïve. In conclusion, our study demonstrates a different pattern of the immune microenvironment in BRAF mutated colon cancer and provides insights into the future use of checkpoint inhibitors in this subgroup of patients.

CD8A and HAPLN3 expression profiling to reveal an immunologic subtype of bladder cancer with favorable survival.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15193-e15193
Author(s):  
Jingjiao Ma ◽  
Ning He ◽  
Jianfei Wang ◽  
Lingyu Wang ◽  
Ge Jin ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Pearson Correlation ◽  
Disease Free Survival ◽  
Correlation Coefficients ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
Specific Gene ◽  
Checkpoint Genes

e15193 Background: At present, immune checkpoint inhibitors (ICI) have demonstrated robust anti-tumor activity with a favorable safety in bladder cancer (BLCA). However, less than half of BLCA patients respond to immunotherapy. We aimed to further delineate the immunologic subtype of BLCA to pick patients who might benefit from ICI treatment. Methods: The RNA-seq and clinical data were collected from The Cancer Genome Atlas (TCGA) data portal (n = 408) and Gene Expression Omnibus (GEO) (GSE48075, n = 142; GSE32894, n = 308). TCGA and GSE48075 cohort are the discovery datasets, and GSE32894 cohort is used for validation. According to the expression of every specific gene ( Gi), patients were divided into two groups using median FPKM as cutpoint value, namely Gi_high and Gi_low, respectively. Combined with CD8A expression, all the patients were divided to four groups as follows: CD8A_high/ Gi_high, CD8A_high/ Gi_low, CD8A_low/ Gi_high, and CD8A_low/ Gi_low. Then we calculated the pearson correlation coefficients between Gi and 13 immune checkpoint genes ( CD274, IDO1, CTLA4, LAG3, CD276, VTCN1, CD70, HAVCR2, CD40, CD47, TNFRSF18, TIGIT, and TNFSF14). Overall or disease free survival of the four groups were compared using the survfit function from the survival R package and P values from log-rank tests were reported. Results: In the discovery cohort, we found CD8A_high/ HAPLN3_low group showed the best overall survival, whereas the CD8A_low/ HAPLN3_high showed the worst (TCGA, p = 0.013; GSE48075, p = 0.012). Additionally, HAPLN3 was positively correlated with 5/13 immune-checkpoint genes: CD274, IDO1, CTLA4, LAG3, HAVCR2 (r > 0.6, p < 0.01). And the same observations were extended in the validation cohort (GSE32894): CD8A_high/ HAPLN3_low group exhibited a favorable survival (p = 0.00059), and HAPLN3 had a strong correlation with the same 5 immune-checkpoint genes (r > 0.6, p < 0.01). Conclusions: The combination of high CD8A and low HAPLN3 expression identified a subtype of BLCA patients with favorable survival and these findings may further help refining the selection of BLCA patients for immunotherapy.

scholarly journals The identification of a potential prognostic model of colon cancer using integrated bioinformatics analysis

2020 ◽  
Author(s):  
Zhengyu Fang ◽  
Sumei Xu ◽  
Yiwen Xie ◽  
Wenxi Yan
Keyword(s):  
Gene Expression ◽  
Colon Cancer ◽  
Prognostic Model ◽  
Predictive Power ◽  
Gene Signature ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
Cancer Prognosis ◽  
Training Dataset ◽  
High Predictive Power

Abstract Background This study aimed to construct prognostic model by screening prognostic gene signature of colon cancer. Methods The gene expression profile data of colon cancer were obtained from The Cancer Genome Atlas (TCGA) and gene expression omnibus (GEO) and differently expressed genes (DEGs) between tumor and control samples were identified. Prognosis-associated genes were then identified and used for the construction of prognostic model. The independent factors that associated with the prognosis of colon in the TCGA cohort was identified. Results Totally, 1153 consistent DEGs were screened out between tumor and normal tissues in the TCGA cohort, GSE44861 and GSE44076 datasets. Among these genes, 12 DEGs were related to the prognosis of colon cancer and were used for constructing the prognostic model. This model presented a high predictive power for the prognosis of colon cancer both in the training dataset and in the validation datasets (AUC > 0.8). Statistical analysis showed that age, pathological T, tumor recurrence, and model status were the independent factors for prognosis of patients with colon cancer in TCGA. Conclusions The 12-gene signature prognostic model had a high predictive power for colon cancer prognosis.

scholarly journals Immunomodulating Therapies in Breast Cancer—From Prognosis to Clinical Practice

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4883
Author(s):  
Marcus Schmidt ◽  
Anne-Sophie Heimes
Keyword(s):  
Breast Cancer ◽  
Immune Responses ◽  
Triple Negative Breast Cancer ◽  
Immune Checkpoint ◽  
Triple Negative ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Tumor Infiltrating Lymphocytes ◽  
Response To Chemotherapy ◽  
Infiltrating Lymphocytes

The role of the immune system in breast cancer has been debated for decades. The advent of technologies such as next generation sequencing (NGS) has elucidated the crucial interplay between somatic mutations in tumors leading to neoantigens and immune responses with increased tumor-infiltrating lymphocytes and improved prognosis of breast cancer patients. In particular, triple-negative breast cancer (TNBC) has a higher mutational burden compared to other breast cancer subtypes. In addition, higher levels of tumor-associated antigens suggest that immunotherapies are a promising treatment option, specifically for TNBC. Indeed, higher concentrations of tumor-infiltrating lymphocytes are associated with better prognosis and response to chemotherapy in TNBC. An important target within the cancer immune cell cycle is the “immune checkpoint”. Immune checkpoint inhibitors (ICPis) block the interaction of certain cell surface proteins that act as “brakes” on immune responses. Recent studies have shown that ICPis improve survival in both early and advanced TNBC. However, this comes at the price of increased toxicity, particularly immune-mediated toxicity. As an alternative approach, individualized mRNA vaccination strategies against tumor-associated neoantigens represent another promising approach leading to neoantigen-specific immune responses. These novel strategies should help to improve treatment outcomes, especially for patients with triple negative breast cancer.

scholarly journals Development of a Novel Immune Infiltration-Based Gene Signature to Predict Prognosis and Immunotherapy Response of Patients With Cervical Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Sihui Yu ◽  
Xi Li ◽  
Jiawen Zhang ◽  
Sufang Wu
Keyword(s):  
Cervical Cancer ◽  
Immune Cell ◽  
Cox Regression ◽  
Patient Survival ◽  
Checkpoint Inhibitors ◽  
Cell Types ◽  
Gene Signature ◽  
The Cancer Genome Atlas ◽  
Cervical Lesions ◽  
Immune Infiltration

Predictive models could indicate the clinical outcome of patients with carcinoma. Cervical cancer is one of the most frequently diagnosed female malignancies. Herein, we proposed an immune infiltration-related gene signature that predicts prognosis of patients with cervical cancer and depicts the immune landscape as well. We utilized the transcriptome data of The Cancer Genome Atlas (TCGA) and estimated the infiltration level of 28 immune cell types. We screened out four immune cell types conducive to patient survival and recognized their shared differentially expressed genes (DEGs). Four core genes (CHIT1, GTSF1L, PLA2G2D, and GNG8) that composed the ultimate signature were identified via univariate and multivariate Cox regression. The optimal model we built up could distinguish patients with cervical cancer into high-score and low-score subgroups. These two subgroups showed disparity in aspects of patient survival, immune infiltration landscape, and response to immune checkpoint inhibitors. Additionally, we found that GTSF1L was decreased gradually along with the severity of cervical lesions, and its potential role in immune contexture and clinical practice were also demonstrated. Our results suggested that the Immunoscore based on four immune-related genes could serve as a supplementary criterion to effectively foresee the survival outcome, tumor infiltration status, and immunotherapy efficacy of cervical cancer patients.

scholarly journals Establishment and Validation of a Genetic Label Associated With M2 Macrophage Infiltration to Predict Survival in Patients With Colon Cancer and to Assist in Immunotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Boyang Xu ◽  
Ziqi Peng ◽  
Guanyu Yan ◽  
Ningning Wang ◽  
Moye Chen ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
The Cancer Genome Atlas ◽  
Macrophage Infiltration ◽  
M2 Macrophage ◽  
High Morbidity ◽  
Consensus Clustering ◽  
M2 Macrophages ◽  
Hub Genes

BackgroundColon cancer is a malignant tumor with high morbidity and mortality. Researchers have tried to interpret it from different perspectives and divided it into different subtypes to facilitate individualized treatment. With the rise in the use of immunotherapy, its value in the field of tumor has begun to emerge. From the perspective of immune infiltration, this study classified colon cancer according to the infiltration of M2 macrophages in patients with colon cancer and further explored the same.MethodsCibersort algorithm was used to analyze the level of immune cell infiltration in patients with colon cancer in The Cancer Genome Atlas (TCGA) database. Weighted gene co-expression network analysis (WGCNA), Consensus Clustering analysis, Lasso analysis, and univariate Kaplan–Meier analysis were used to screen and verify the hub genes associated with M2 macrophages. Principal component analysis (PCA) was used to establish the M2 macrophage-related score (M2I Score). The correlation between M2I Score and somatic cell variation and microsatellite instability (MSI) were analyzed. Furthermore, the correlation between M2 macrophage score and differences in immunotherapy sensitivity was also explored.ResultsM2 macrophage infiltration was associated with poor prognosis. Four hub genes (ANKS4B, CTSD, TIMP1, and ZNF703) were identified as the progression-related genes associated with M2 macrophages. A stable and accurate M2I Score for M2 macrophages used in colon adenocarcinoma was determined based on four hub genes. The M2I Score was positively correlated with the tumor mutation load (TMB). The M2I Score of the group with high instability of microsatellites was higher than that of the group with low instability of microsatellites and microsatellite-stable group. Combined with the Cancer Immunome Atlas database, we concluded that patients with high M2I Scores were more sensitive to programmed cell death protein 1 (PD-1) inhibitors and PD-1 inhibitors combined with cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) inhibitors. The low-rating group may have better efficacy without immune checkpoint inhibitors or with CTLA4 inhibitors alone.ConclusionFour prognostic hub genes associated with M2 macrophages were screened to establish the M2I Score. Patients were divided into two subgroups: high M2I Score group and low M2I Score group. TMB, MSI, and sensitivity to immunotherapy were higher in the high-rated group. PD-1 inhibitors or PD-1 combined with CTLA-4 inhibitors are preferred for patients in the high-rated group who are more sensitive to immunotherapy.

scholarly journals PTEN Alterations as a Potential Mechanism for Tumor Cell Escape from PD-1/PD-L1 Inhibition

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1318 ◽  
Author(s):  
Cretella ◽  
Digiacomo ◽  
Giovannetti ◽  
Cavazzoni
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Tumor Infiltrating Lymphocytes ◽  
Suppressor Gene ◽  
Pten Expression ◽  
Advanced Cancer Patients ◽  
Pten Loss ◽  
Programmed Death

The recent approval of immune checkpoint inhibitors drastically changed the standard treatments in many advanced cancer patients, but molecular changes within the tumor can prevent the activity of immunotherapy drugs. Thus, the introduction of the inhibitors of the immune checkpoint programmed death-1/programmed death ligand-1 (PD-1/PD-L1), should prompt deeper studies on resistance mechanisms, which can be caused by oncogenic mutations detected in cancer cells. PTEN, a tumor suppressor gene, dephosphorylates the lipid signaling intermediate PIP3 with inhibition of AKT activity, one of the main effectors of the PI3K signaling axis. As a consequence of genetic or epigenetic aberrations, PTEN expression is often altered, with increased activation of PI3K axis. Interestingly, some data confirmed that loss of PTEN expression modified the pattern of cytokine secretion creating an immune-suppressive microenvironment with increase of immune cell populations that can promote tumor progression. Moreover, PTEN loss may be ascribed to reduction of tumor infiltrating lymphocytes (TILs), which can explain the absence of activity of immune checkpoint inhibitors. This review describes the role of PTEN loss as a mechanism responsible for resistance to anti PD-1/PD-L1 treatment. Moreover, combinatorial strategies between PD-1/PD-L1 inhibitors and PI3K/AKT targeting drugs are proposed as a new strategy to overcome resistance to immune checkpoint inhibition.

scholarly journals Establishment and Validation of a Comprehensive Prognostic Model for Patients With HNSCC Metastasis

2021 ◽  
Vol 12 ◽  
Author(s):  
Yajun Shen ◽  
Lingyu Li ◽  
Yunping Lu ◽  
Min Zhang ◽  
Xin Huang ◽  
...  
Keyword(s):  
High Performance ◽  
Prognostic Model ◽  
Immune Cell ◽  
Enrichment Analysis ◽  
Tumor Stage ◽  
Gene Signature ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
Risk Level ◽  
Gene Sets

ObjectiveTo identify biomarkers related to head and neck squamous cell carcinoma (HNSCC) metastasis and establish a prognostic model for patients with HNSCC.MethodsHNSCC mRNA expression data of metastasis and non-metastatic samples were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. After screening the differentially expressed genes (DEGs) in the two datasets, a prognostic model, including clinical factors and biomarkers, was established, and verified in 36 samples of HNSCC by quantitative real-time transcription (qRT)-PCR. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene sets enrichment analysis (GSEA) were consulted to explore the functions of the DEGs.ResultsIn total, 108 DEGs were identified. GSEA, GO, and KEGG analyses showed that these DEGs were mainly involved in the proliferation and metastasis of HNSCC. Six genes that were significantly related to metastasis, immune cell infiltration and prognosis were further identified to construct a prognostic gene signature. The reliability of the gene signature was verified in 36 samples of HNSCC. A prognostic model, including tumor stage, risk level, and a nomogram for prediction were further established. Receiver operating characteristic (ROC) analysis, decision curve analysis (DCA), C-index, and calibration plots showed that the model and nomogram perform well.ConclusionWe constructed a six-gene signature and a nomogram with high performance in predicting the prognosis of patients with HNSCC metastasis.

scholarly journals Novel Epigenetic Eight-Gene Signature Predictive of Poor Prognosis and MSI-Like Phenotype in Human Metastatic Colorectal Carcinomas

Cancers ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 158
Author(s):  
Valentina Condelli ◽  
Giovanni Calice ◽  
Alessandra Cassano ◽  
Michele Basso ◽  
Maria Grazia Rodriquenz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Poor Prognosis ◽  
Cpg Island ◽  
Colon Adenocarcinoma ◽  
Gene Signature ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
Cpg Island Methylator Phenotype ◽  
Prognostic Information ◽  
Global Methylation

Epigenetics is involved in tumor progression and drug resistance in human colorectal carcinoma (CRC). This study addressed the hypothesis that the DNA methylation profiling may predict the clinical behavior of metastatic CRCs (mCRCs). The global methylation profile of two human mCRC subgroups with significantly different outcome was analyzed and compared with gene expression and methylation data from The Cancer Genome Atlas COlon ADenocarcinoma (TCGA COAD) and the NCBI GENE expression Omnibus repository (GEO) GSE48684 mCRCs datasets to identify a prognostic signature of functionally methylated genes. A novel epigenetic signature of eight hypermethylated genes was characterized that was able to identify mCRCs with poor prognosis, which had a CpG-island methylator phenotype (CIMP)-high and microsatellite instability (MSI)-like phenotype. Interestingly, methylation events were enriched in genes located on the q-arm of chromosomes 13 and 20, two chromosomal regions with gain/loss alterations associated with adenoma-to-carcinoma progression. Finally, the expression of the eight-genes signature and MSI-enriching genes was confirmed in oxaliplatin- and irinotecan-resistant CRC cell lines. These data reveal that the hypermethylation of specific genes may provide prognostic information that is able to identify a subgroup of mCRCs with poor prognosis.

scholarly journals Expression of Immune Checkpoint Regulators IDO, VISTA, LAG3, and TIM3 in Resected Pancreatic Ductal Adenocarcinoma

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2689
Author(s):  
Felix Popp ◽  
Ingracia Capino ◽  
Joana Bartels ◽  
Alexander Damanakis ◽  
Jiahui Li ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Immune Checkpoint ◽  
Patient Survival ◽  
Checkpoint Inhibitors ◽  
Tumor Infiltrating Lymphocytes ◽  
Ductal Adenocarcinoma ◽  
Lymph Node Status ◽  
Clinicopathologic Parameters ◽  
Survival Differences ◽  
Infiltrating Lymphocytes

Pancreatic cancer features elaborate mechanisms of immune evasion. The potential of new immune molecules was explored to restore the antitumor immune response. If these immune molecules are associated with poor survival, specific drugs could take effect. Here, we analyze the expression of VISTA, LAG3, IDO, and TIM3 on tumor-infiltrating lymphocytes (TILs) and its impact on patient survival. We analyzed 153 pancreatic cancer patients from the prospectively managed database of the multicentered PANCALYZE study. Immunohistochemistry on a tissue microarray assessed VISTA, LAG3, IDO, and TIM3 expression of TILs from the patients undergoing primary resection. Complementarily, we analyzed publicly available transcriptomic data (n = 903). Successful completion of chemotherapy, and lymph node status were independent predictors of survival in the multivariate analysis of the clinicopathologic parameters. Fifteen tumors were exclusively VISTA-positive, thirteen tumors expressed VISTA together with TIM3, and ten tumors expressed VISTA together with IDO. Patients featuring tumors with high numbers of IDO-positive TILs had better patient survival (p = 0.037). VISTA, LAG3, and TIM3 expression did not correlate with survival. The analysis of publicly available data did not show survival differences. Tumors rarely co-express more than two immune molecules at the same time, and VISTA is most frequently co-expressed. Although IDO generally inhibits T-cell proliferation, a high expression of IDO was associated with improved survival. We expect immune checkpoint inhibitors against VISTA, LAG3, and TIM3 to be inefficient in a clinical application.

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