Cell Infiltration In Cancer Research Articles

CAV1 is a prognostic predictor for patients with idiopathic pulmonary fibrosis and lung cancer

The extremely high mortality of both lung cancer and Idiopathic pulmonary fibrosis (IPF) is a global threat. Early detection and diagnosis can reduce their mortality. Since fibrosis is a necessary process of cancer, identifying the common potential prognostic genes involved in these two diseases will significantly contribute to disease prevention and targeted therapy. Microarray datasets of IPF and lung cancer were extracted from the GEO database. GEO2R was exploited to retrieve the differentially expressed genes (DEGs). The intersecting DEGs were obtained by the Venn tool. DAVID tools were used to perform GO and KEGG pathway enrichment analysis of DEGs. Then, the Kaplan-Meier plotter was employed to determine the prognostic value and verify the expression, pathological stage, and phosphorylation level of the hub gene in the TCGA and GTEx database. Finally, the extent of immune cell infiltration in lung cancer was estimated by the TIMER2 tool. The Venn diagram revealed 1 upregulated gene and 15 downregulated genes from GSE32863, GSE43458, GSE118370, and GSE75037 of lung cancer, as well as GSE2052 and GSE53845 of IPF. CytoHubba identified the top three genes [TEK receptor tyrosine kinase (TEK), caveolin 1 (CAV1), and endomucin (EMCN)] as hub genes following the connectivity degree. Survival analysis claimed the association of only TEK and CAV1 expression to both overall survival (OS) and first progression (FP). Pathological stage analyses revealed the relationship of only CAV1 expression to the pathological stage and the significant correlation of only CAV1 phosphorylation expression level for lung cancer. Furthermore, a statistically positive correlation was observed between the immune infiltration of cancer-associated fibroblasts, endothelial, and neutrophils with the CAV1 expression in lung cancer, whereas the contradictory result was noted for the immune infiltration of T cell follicular helper. Early detection and diagnostic potential of lung cancer are ameliorated by the combined selection of key genes among IPF and lung cancer.

EFNA3 Is a Prognostic Biomarker Correlated With Immune Cell Infiltration and Immune Checkpoints in Gastric Cancer.

Background: Ephrin A3 (EFNA3), like most genes in the ephrin family, plays a central role in embryonic development and can be dysregulated in a variety of tumors. However, the relationship between EFNA3 and gastric cancer (GC) prognosis and tumor-infiltrating lymphocytes remains unclear. Methods: Tumor Immune Estimation Resource (TIMER) and Gene Expression Profiling Interactive Analysis 2 (GEPIA2) were used to analyze the expression of EFNA3. Kaplan-Meier plots and GEPIA2 were used to evaluate the relationship between EFNA3 expression and GC prognosis. Univariable survival and multivariate Cox analyses were used to compare various clinical characteristics with survival. LinkedOmics database was used for gene set enrichment analysis (GSEA). TIMER database and CIBERSORT algorithm were used to examine the relationship between EFNA3 expression and immune infiltration in GC and to explore cumulative survival in GC. The relationship between EFNA3 and immune checkpoints was examined using cBioPortal genomics analysis. Finally, EFNA3 expression in GC cells and tissues was assayed using quantitative real-time polymerase chain reaction. Results: EFNA3 expression differs in a variety of cancers, and EFNA3 expression was higher in GC tissue than normal gastric tissue. GC patients with high expression of EFNA3 had worse overall survival, disease-free survival, and first progression. Multivariate analysis identified EFNA3 as an independent prognostic factor for GC. GSEA identified ribosome, cell cycle, ribosome biogenesis in eukaryotes, and aminoacyl-tRNA biosynthesis pathways as differentially enriched in patients with high EFNA3 expression. B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells were significantly negatively correlated with a variety of immune markers. EFNA3 participates in changes in GC immune checkpoint markers in a collinear manner. EFNA3 expression in HGC-27, AGS, MKN45, and NCI-N87 was cell lines higher than that in GES-1, and patients with high expression of EFNA3 had a worse prognosis. Conclusion: EFNA3 can be used as a prognostic and immune infiltration and checkpoint marker in GC patients.

N6-Methyladenosine-Related lncRNAs as potential biomarkers for predicting prognoses and immune responses in patients with cervical cancer

BackgroundSeveral recent studies have confirmed epigenetic regulation of the immune response. However, the potential role of RNA N6-methyladenosine (m6A) modifications in cervical cancer and tumour microenvironment (TME) cell infiltration remain unclear.ResultsWe evaluated and analysed m6A modification patterns in 307 cervical cancer samples from The Cancer Genome Atlas (TCGA) dataset based on 13 m6A regulators. Pearson correlation analysis was used to identify lncRNAs associated with m6A, followed by univariate Cox regression analysis to screen their prognostic role in cervical cancer patients. We also correlated TME cell infiltration characteristics with modification patterns. We screened six m6A-associated lncRNAs as prognostic lncRNAs and established the prognostic profile of m6A-associated lncRNAs by least absolute shrinkage and choice of operator (LASSO) Cox regression. The corresponding risk scores of the patients were derived based on their prognostic features, and the correlation between this feature model and disease prognosis was analysed. The prognostic model constructed based on the TCGA-CESC (The Cancer Genome Cervical squamous cell carcinoma and endocervical adenocarcinoma) dataset showed strong prognostic power in the stratified analysis and was confirmed as an independent prognostic indicator for predicting the overall survival of patients with CESC. Enrichment analysis showed that biological processes, pathways, and markers associated with malignancy were more common in the high-risk subgroup. Risk scores were strongly correlated with the tumour grade. ECM receptor interactions and pathways in cancer were enriched in Cluster 2, while oxidative phosphorylation and other biological processes were enriched in Cluster 1. The expression of immune checkpoint molecules, including programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1), was significantly increased in the high-risk subgroup, suggesting that this prognostic model could be a predictor of immunotherapy.ConclusionsThis study reveals that m6A modifications play an integral role in the diversity and complexity of TME formation. Assessing the m6A modification patterns of individual tumours will help improve our understanding of TME infiltration characteristics and thus guide immunotherapy more effectively. We also developed an independent prognostic model based on m6A-associated lncRNAs as a predictor of overall survival, which can also be used as a predictor of immunotherapy.

Decreased TMPRSS2 expression by SARS-CoV-2 predicts the poor prognosis of lung cancer patients through metabolic pathways and immune infiltration.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread around the world and became a global pandemic in 2020. One promising drug target for SARS-CoV-2 is the transmembrane protease serine 2 (TMPRSS2). This study was designed to explore the expression status, prognostic significance and molecular functions of TMPRSS2 in lung cancer. TMPRSS2 expression was investigated using the TIMER, Oncomine, UALCAN, GEO, HPA and TCGA databases. The prognostic value of TMPRSS2 was examined using Cox regression and a nomogram. KEGG, GO and GSEA were performed to investigate the cellular function of TMPRSS2 in lung cancer. The relationship between TMPRSS2 and immune infiltration was determined using the TIMER and CIBERSORT algorithms. TMPRSS2 mRNA and protein expression was significantly reduced in lung cancer. Decreased TMPRSS2 expression and increased DNA methylation of TMPRSS2 were associated with various clinicopathological parameters in patients with lung cancer. Low TMPRSS2 mRNA expression also correlated with poor outcome in lung cancer patients. Moreover, a nomogram was constructed and exhibited good predictive power for the overall survival of lung cancer patients. KEGG and GO analyses and GSEA implied that multiple immune- and metabolism-related pathways were significantly linked with TMPRSS2 expression. Intriguingly, TMPRSS2 expression associated with immune cell infiltration in lung cancer. More importantly, TMPRSS2 expression was markedly decreased in SARS-CoV-infected cells. These findings indicate that TMPRSS2 may be a promising prognostic biomarker and therapeutic target for lung cancer through metabolic pathways and immune cell infiltration.

Characterization of m6A Regulator-Mediated Methylation Modification Patterns and Tumor Microenvironment Infiltration in Ovarian Cancer.

Introduction: Studies have demonstrated the epigenetic regulation of immune responses in various cancers. However, little is known about the RNA N6-methyladenosine (m6A) modification patterns of the microenvironment (TME) cell infiltration in ovarian cancer (OC). Methods: We evaluated the correlation between m6A modification patterns and TME cell infiltration based on 459 OC samples from the Cancer Genome Atlas and Gene-Expression Omnibus database. We constructed an m6Ascore system to quantify m6A modification patterns using principal component analysis. Results: Based on unsupervised clustering, three m6A modification patterns were identified. Gene set variation analysis showed that the antigen presentation signal pathway, the NOTCH signaling pathway, and the metabolism-related pathway differed significantly across m6A modificaiton patterns. The m6Ascore is closely correlated with TME cell infiltration. OC patients with lower m6Ascores had worse outcomes. There was better risk stratification with combined m6Ascore and tumor mutation burden. The responses to immune checkpoint inhibitor treatment significantly differed between high and low m6Ascore groups. Conclusion: M6A modification plays an essential role in TME cell infiltration in OC. Evaluating the m6A modification patterns in OC patients could enhance our understanding of TME infiltration characterization and guide immunotherapy strategies.

INHBA is a Prognostic Biomarker and Correlated With Immune Cell Infiltration in Cervical Cancer.

Background: Inhibin A (INHBA), a member of the TGF-β superfamily, has been shown to be differentially expressed in various cancer types and is associated with prognosis. However, its role in cervical cancer remains unclear. Methods: We aimed to demonstrate the relationship between INHBA expression and pan-cancer using The Cancer Genome Atlas (TCGA) database. Next, we validated INHBA expression in cervical cancer using the Gene Expression Omnibus (GEO) database, including GSE7803, GSE63514, and GSE9750 datasets. Enrichment analysis of INHBA was performed using the R package “clusterProfiler.” We analyzed the association between immune infiltration level and INHBA expression in cervical cancer using the single-sample gene set enrichment analysis (ssGSEA) method by the R package GSVA. We explored the association between INHBA expression and prognosis using the R package “survival”. Results: Pan-cancer data analysis showed that INHBA expression was elevated in 19 tumor types, including cervical cancer. We further confirmed that INHBA expression was higher in cervical cancer samples from GEO database and cervical cancer cell lines than in normal cervical cells. Survival prognosis analysis indicated that higher INHBA expression was significantly associated with reduced Overall Survival (p = 0.001), disease Specific Survival (p = 0.006), and Progression Free Interval (p = 0.001) in cervical cancer and poorer prognosis in other tumors. GSEA and infiltration analysis showed that INHBA expression was significantly associated with tumor progression and some types of immune infiltrating cells. Conclusion: INHBA was highly expressed in cervical cancer and was significantly associated with poor prognosis. Meanwhile, it was correlated with immune cell infiltration and could be used as a promising prognostic target for cervical cancer.

Identification of a DNA repair 9-gene signature for the overall survival prediction of pancreatic cancer

BackgroundPancreatic cancer (PC) is one of the deadliest malignant tumors with poor prognosis. DNA repair genes can be promising candidate biomarkers in PC. The aim of this study was to generate and clinically validate a novel gene signature to effectively predict the prognosis of patients with PC. MethodsThe PC-related data of cancer genome atlas database and the GSE62452, GSE85916 of the gene expression omnibus database were downloaded for signature and further validation. According to the risk score, Patients were classified into high and low risk score groups. We analyzed drug sensitivity base on genomics of drug sensitivity in cancer and immune cell infiltration via CIBERSORT between the two groups. Gene set variation Analysis was performed to analyze signaling pathways affecting prognosis. ResultsNine genes (F5, CD36, TRIM29, VCAM1, ANO1, ERBB3, MMP28, NEK2 and MET) were identified to construct a prognostic model. Patients with lower risk score had significantly favorable overall survival in the TCGA database, GSE62452 and GSE85916 dataset (p < 0.05). GSVA analysis showed differences in 13 important signaling pathways between high and low risk score groups. Immune-modulating factors (ADORA2A, CD160, KDR, BTLA) were highly expressed in the low-risk group. The risk score significantly affected the sensitivity of patients to Gefitinib and Dasatinib (p < 0.005) and associated with overall survival and grade (p < 0.05). ConclusionThis study evaluated a potential prognostic signature base on nine DNA repair genes and provides a way to explore the mechanism of DNA repair genes and immunotherapy in pancreatic cancer.

Biological features of canine cancer-associated fibroblasts and their influence on cancer cell invasion.

Cancer-associated fibroblasts (CAFs) play an essential role in tumor invasion and metastasis. In dogs, the biological features of CAFs have not been well characterized. The purpose of this study was to investigate differences in the biological activities of canine CAFs and normal fibroblasts (NFs), and their influence on the migration and invasion of cancer cells. Canine CAFs and NFs were harvested from surgically-resected malignant epithelial tumor tissues and skin tissues of dogs. A wound-healing assay was conducted to compare the migratory and invasive abilities of canine CAFs and NFs. The results of this study showed that canine CAFs have a greater migratory and invasive ability than NFs. To observe the indirect and direct interactions between fibroblasts and cancer cells, Boyden chamber assay and 3D co-culture with collagen gel were conducted. The number of migrated and infiltrated cancer cells co-cultured with canine CAFs was greater than that with NFs. In the 3D co-culture, cancer cells showed noteworthy proliferation on the surface of gels containing canine CAFs and invasion into the gel. On the other hand, no infiltration of cancer cells into the gel containing NFs was observed. It was suggested that canine CAFs activate migration and invasion of cancer cells and promote the infiltration of cancer cells into collagen gels.

Impact of Central Airway Infiltration Type in Primary Lung Cancer Patients Treated With Sleeve Lobectomy.

There are two types of lung cancer cell infiltration into the central airway. One is when a centrally located lung cancer directly infiltrates the central airway and the other is when cancer cells in the metastatic hilar lymph node infiltrate the central airway. We aimed to identify the impact of central airway infiltration type on the clinical features of patients undergoing sleeve lobectomy. The clinical courses of 58 primary lung cancer patients who underwent sleeve lobectomy between January 2010 and December 2020 were investigated. Primary tumors directly infiltrated into the central airway in 42 patients, whereas 16 patients had infiltration of cancer cells from the metastatic hilar lymph node. Primary tumor infiltration was a poor prognostic factor according to both univariate (p=0.016) and multivariate analyses (p=0.042). Operation times (p=0.240) and incidences of adverse events (p=0.926) were not associated with the type of central airway infiltration. The type of airway infiltration was an independent poor prognostic factor after sleeve lobectomy in primary lung cancer patients. Our findings may guide the selection of optimal treatments for this patient population.

The role of miR-4469 as a tumor suppressor regulating inflammatory cell infiltration in colorectal cancer

BackgroundMicroRNA (miRNA) regulates gene expression posttranscriptionally, and some of them function in tumor suppression and can be used in drug development. As a result, identifying and screening miRNAs that suppress tumors would be a significant addition to tumor treatment. MethodsIn this study, we analyzed the miRNA expression profile of colorectal cancer (CRC), constructed a negative regulatory network of the miRNA-target genes, and identified miR-4469 as one of the key tumor suppressors miRNAs. We analyzed the expression and survival of miR-4469 in pan-cancer, experimentally verified the expression level of miR-4469 in CRC cells and the effect on CRC cell proliferation and migration. We screened miR-4469 target genes for enrichment analysis and immune cell infiltration analysis and validated target gene expression to clarify the regulatory mechanisms involved in miR-4469. ResultsmiR-4469 was more highly expressed in normal colorectum tissues compared to CRC tissues and correlated with survival time in patients with multiple cancers. It was shown that miR-4469 was highly expressed in normal colon cells and miR-4469 expression could inhibit the proliferation and migration of CRC cells. In addition, studies on the mechanism showed that miR-4469 function is mainly related to the regulation of inflammatory cell infiltration, and the key target genes of miR-4469 in this process are SLC2A3, FGR, PLEKHO2, and MYO1F. ConclusionmiR-4469 is a tumor suppressor in CRC, and its regulatory mechanism mainly affects the infiltration of inflammatory cells in the cancer tissue.

Stereotaxic Implantation of F98 Cells in Fischer Rats: A Syngeneic Model to Investigate Photodynamic Therapy Response in Glioma.

When investigating the promise of novel therapeutic modalities, the choice of an appropriate and reproducible in vivo model is critical to determine the relevance of the findings. In the case of glioblastoma, a high-grade glioma tumor that is clinically characterized by a high infiltrative pattern, no existing model exactly mimics the clinical features of these tumors. However, a syngeneic rat model of glioblastoma in which F98 cells are orthotopically implanted can recapitulate most of the characteristics of glioma as observed in patients, including a highly aggressive nature, a high degree of infiltration of cancer cells into healthy tissue, and a strong resistance to commonly used treatments including radiotherapy and chemotherapy. Here, we provide a detailed protocol to stereotaxically implant F98 cells in the rat brain and obtain a reproducible and clinically representative glioma model in rodents.

LncRNA PCAT14 Is a Diagnostic Marker for Prostate Cancer and Is Associated with Immune Cell Infiltration.

Objective To investigate the relationship between the long noncoding RNA (lncRNA) Prostate cancer-associated transcription factors 14 (PCAT14) and the clinical characteristics of prostate cancer and immune cell infiltration. Methods The relationship between PCAT14 expression and the clinicopathological characteristics of prostate cancer was analyzed based on The Cancer Genome Atlas (TCGA) database. Receiver operating characteristic (ROC) curves were used to evaluate the value of PCAT14 as a diagnostic marker for prostate cancer. The relationship between PCAT14 and immune cell infiltration was analyzed to explore the effect of PCAT14 on the immune-related functions of prostate cancer. Results The ROC curve showed that PCAT14 had a significant diagnostic ability (area under curve = 0.818) for prostate cancer. A reduced expression of PCAT14 in prostate cancer was related to T stage, N stage, primary therapy outcome, residual tumor, Gleason score, and age. The expression of PCAT14 was independently associated with the progression-free interval in prostate cancer patients. The infiltration of immune cells in prostate cancer showed a significant negative correlation between the expression of PCAT14 and plasmacytoid dendritic cells, activated dendritic cells, regulatory T cells, and neutrophils. Conclusions PCAT14 is highly expressed in prostate cancer and is expected to be a diagnostic marker. PCAT14 might promote the development of prostate cancer through chemokines, antimicrobials, and cytokines that affect the infiltration of immune cells.

Basis for diurnal exacerbation of neuropathic pain hypersensitivity and its application for drug development.

In addition to diurnal rhythms in physiology and behavior, a variety of pathological conditions also exhibit marked day-night changes in symptom intensity, exemplified by allergic rhinitis, arthritis, asthma, myocardial infarction, congestive heart failure, stroke and chronic pain disorders. Currently, novel therapeutic approaches are facilitated by the development of chemical compounds targeted to key proteins that cause diurnal exacerbation of pathological events. Neuropathic pain is a chronic condition that occurs by tumor-induced nerve compression, cancer cell infiltration into the nerve, diabetes and herpes virus infection. One troublesome hallmark symptom of neuropathic pain is hypersensitivity to normally innocuous stimuli known as 'mechanical allodynia' that is often refractory to common analgesic therapies. Millions of patients worldwide presently endure neuropathic pain. We summarize the recent insights gained into the mechanism of diurnal exacerbation of neuropathic pain hypersensitivity and introduce the strategy of circadian clock-based drug development.

Comprehensive Analysis of Innate Immunophenotyping Based on Immune Score Predicting Immune Alterations and Prognosis in Breast Cancer Patients.

Breast cancer is the most common cancer, with the highest mortality rate and the most diagnosed cancer type in women worldwide. To identify the effect innate immune checkpoint for breast cancer immunotherapy, the innate immune prognostic biomarkers were selected through the ICI score model and the risk model in breast cancer patients. Moreover, the reliability and accuracy of the ICI score model and the risk model were further examined through the analysis of breast cancer prognosis and immune cell infiltration. The pan cancer analysis further confirmed and selected CXCL9 as the key innate immune checkpoint for breast cancer immunotherapy and identified three small molecular drugs for target CXCL9 through molecular docking analysis. In summary, CXCL9 significantly correlated with the prognostic of breast cancer and immune cell infiltration and could be innate immune checkpoint for breast cancer immunotherapy.

Characteristics of CD8+ T cell infiltration in colorectal cancer and their correlation with prognosis

Objective: As cytotoxic T cells, CD8+ T lymphocytes can kill tumor cells by releasing perforin and other effector molecules, but the correlation between their infiltration level and the prognosis of colorectal cancer varies in previous studies. This study aims to explore the distribution of CD8+T cells in tumor center and invasive margin of colorectal cancer, and to analyze their correlation with the prognosis of patients. Methods: A retrospective cohort study was used to analyze the clinicopathological features of 221 patients with colorectal cancer from the colorectal cancer pathological database of the Sixth Affiliated Hospital of Sun Yat-sen University between 2009 and 2012. Case inclusion criteria: (1) colorectal cancers confirmed by postoperative pathology; (2) patients with follow-up data. Exclusion criteria: (1) multiple primary cancers; (2) inflammatory bowel disease, Lynch syndrome or familial adenomatous polyposis; (3) no available paraffin slides; (4) patients receiving preoperative radiotherapy or chemotherapy. A total of 221 patients met the criteria. Immunohistochemical staining was used to count the CD8+ T cells in tumor center and invasive margin in the paraffin slides. Meanwhile the relative expression of CD8B gene in 22 fresh freeze samples of colorectal cancer was detected. Then the correlation of the expression with CD8+T cell density was examined. The patients were divided into high and low infiltration groups according to the level of CD8+T cells. Log-rank test was applied to compare the overall survival of the two groups of patients, and Cox regression analysis was used to adjust the prognostic significance of CD8+T cell infiltration. Results: There were 118 males and 103 females. In 221 slides, CD8+T cells infiltrating in invasive margin were more than those in tumor center [median (range): 37(0-141) / field vs. 14(0-106) / field, Z=-11.985, P<0.001], and the number of CD8+T cell in the tumor center was positively correlated with those in invasive margin (r=0.610, P<0.001). The number of CD8+ T cell in tumor center was positively correlated with the relative expression of CD8B gene (r=0.524, P=0.012). Survival analysis showed that the overall survival of the high infiltration group was better than that of the low infiltration group both in tumor center and invasive margin (median survival: 84.1 months vs. 73.5 months, P<0.001; 84.2 months vs. 75.9 months, P=0.002). Cox regression analysis revealed that high CD8+T cell infiltration in tumor center was an independent protective factor of overall survival (HR=0.369, 95% CI: 0.168-0.812, P=0.013). Conclusions: The infiltration level of CD8+T cells in tumor center is lower than that in invasive margin, and they are positively correlated. The level of CD8+ T cell infiltration in tumor center is related to overall survival and can be used as a potential pronostic marker.

Signature of arylacetamide deacetylase expression is associated with prognosis and immune infiltration in ovarian cancer.

ObjectiveThe role of the protein-coding gene arylacetamide deacetylase (AADAC) in the prognostication of ovarian cancer remains uncertain. We aimed to identify and validate its prognostic value using integrated bioinformatics analyses.MethodsGene expression profiles of RNA-sequencing and microarray data were retrieved from The Cancer Genome Atlas and Gene Expression Omnibus. Univariate and multivariate Cox regression models were used to evaluate the prognostic value of gene expression. The predictive accuracy of the gene signature model was evaluated using a time-dependent receiver operating characteristic (ROC) curve. In addition, the correlation between immune infiltration and AADAC was identified. A nomogram of the gene signature with clinical parameters was constructed to estimate the clinical application of the signature for survival prediction in patients with ovarian cancer.ResultsUnivariate and multivariate Cox regression analyses in the training and validation cohorts indicated that a high AADAC expression signature was significantly and independently correlated with better survival outcomes in ovarian cancer. AADAC upregulation positively correlated with the infiltration of CD4+ memory T cells. Immunological signature gene sets were significantly enriched in CD4+ T cell regulation pathways. The area under the curve of the time-dependent ROC for overall survival indicated that the constructed nomogram had a moderate predictive ability for prognostic prediction in ovarian cancer.Conclusion AADAC expression signature significantly and independently correlated with the survival outcome and CD4+ memory T cell infiltration in ovarian cancer, indicating its potential applicability in the prediction of prognosis and immunotherapy efficacy.

CRYAB predicts clinical prognosis and is associated with immunocyte infiltration in colorectal cancer.

BackgroundαB-Crystallin (CRYAB) is differentially expressed in various tumors. However, the correlation between CRYAB and immune cell infiltration in colorectal cancer (CRC) remains unclear.Materials & MethodsKaplan–Meier survival curves in The Cancer Genome Atlas (TCGA) were used to evaluate the relationship between CRYAB expression and both overall survival and progression-free survival. The relationships between CRYAB expression and infiltrating immune cells and their corresponding gene marker sets were examined using the TIMER database.ResultsThe expression of CRYAB was lower in CRC tumor tissues than in normal tissues (P < 0.05). High CRYAB gene expression and high levels of CRYAB gene methylation were correlated with high-grade malignant tumors and more advanced tumor, nodes and metastasis (TNM) cancer stages. In addition, in colorectal cancer, there was a positive correlation between CRYAB expression and immune infiltrating cells including neutrophils, macrophages, CD8 + T cells, and CD4 + T cells, as well as immune-related genes including CD2, CD3D, and CD3E. Methylation sites such as cg13084335, cg15545878, cg13210534, and cg15318568 were positively correlated with low expression of CRYAB.ConclusionBecause CRYAB likely plays an important role in immune cell infiltration, it may be a potential tumor-suppressor gene in CRC and a potential novel therapeutic target and predictive biomarker for colorectal cancer (CRC).

SH2D4A downregulation due to loss of chromosome 8p is associated with poor prognosis and low T cell infiltration in colorectal cancer.

Colorectal cancer (CRC) develops through chromosomal instability (CIN) or microsatellite instability (MSI) due to deficient mismatch-repair (dMMR). We aimed to characterise novel cancer-associated genes that are downregulated upon malignant transformation in microsatellite stable (MSS) CRCs, which typically exhibit CIN with proficient mismatch-repair (pMMR). Comprehensive screening was conducted on adenomas, MSI/MSS CRCs and cell lines, followed by copy number analysis, and their genetic and prognostic relevance was confirmed in microarray and RNA-seq cohorts (n = 3262, in total). Immunohistochemistry for SH2D4A was performed in 524 specimens of adenoma, carcinoma in situ and dMMR/pMMR CRC. The functional role of SH2D4A was investigated using CRC cell lines. A set of 11 genes, including SH2D4A, was downregulated during the adenoma-carcinoma sequence in MSS/CIN CRCs, mainly due to chromosome 8p deletions, and their negative prognostic impact was validated in independent cohorts. All adenomas were SH2D4A positive, but a subset of CRCs (5.3%) lacked SH2D4A immunohistochemical staining, correlating with poor prognosis and scarce T cell infiltration. SH2D4A depletion did not affect cell proliferation or IL-6-induced STAT3 phosphorylation. Our findings suggest that downregulation of multiple genes on chromosome 8p, including SH2D4A, cooperatively contribute to tumorigenesis, resulting in the immune cold tumour microenvironment and poor prognosis.

HLA Class II Histocompatibility Antigen γ Chain (CD74) Expression Is Associated with Immune Cell Infiltration and Favorable Outcome in Breast Cancer.

Simple SummaryCD74 is a transmembrane protein normally expressed in immune cells, and aberrantly expressed in cancer cells. Although CD74 overexpression is mostly associated with hematologic malignancies, some studies have also reported CD74 expression in breast cancer especially associated to the triple negative subtype and metastatic breast cancer. The triple-negative breast cancer is generally more aggressive and with a poorer prognosis than the other subtypes. Immunotherapy holds great promise in clinical management of breast cancer, and CD74 may play a regulatory role in immune system responses. Our results showed that CD74 is associated with expression of programmed cell death ligand 1 (PD-L1), which in turn is involved in preventing anticancer immune responses. Overall, our results indicate that CD74 may be a therapeutic target for the treatment of breast cancer patients, in particular in triple negative breast cancer and metastatic breast cancers, where CD74 is commonly overexpressed.The triple-negative breast cancer (TNBC) subtype, defined as negative for ER, PgR, and HER2, is biologically more aggressive and with a poorer prognosis than the other subtypes, in part due to the lack of suitable targeted therapies. Consequently, identification of any potential novel therapeutic option, predictive and/or prognostic biomarker, or any other relevant information that may impact the clinical management of this group of patients is valuable. The HLA class II histocompatibility antigen γ chain, or cluster of differentiation 74 (CD74), has been associated with TNBCs, and poorer survival. However, discordant results have been reported for immunohistochemical studies of CD74 expression in breast cancer. Here we report validation studies for use of a novel CD74 antibody, UMAb231. We used this antibody to stain a TMA including 640 human breast cancer samples, and found no association with the TNBC subtype, but did find a positive correlation with outcome. We also found associations between CD74 expression and immune cell infiltration, and expression of programmed death ligand 1 (PD-L1). Given that CD74 may play a role in innate immune system responses and the potential of immunotherapy as a viable treatment strategy for TNBCs, CD74 expression may have predictive value for immune checkpoint therapies.

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

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.