scholarly journals Spatial clustering of CD68+ tumor associated macrophages with tumor cells is associated with worse overall survival in metastatic clear cell renal cell carcinoma

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0245415
Author(s):  
Nicholas H. Chakiryan ◽  
Gregory J. Kimmel ◽  
Youngchul Kim ◽  
Ali Hajiran ◽  
Ahmet M. Aydin ◽  
...  
Keyword(s):  
Overall Survival ◽  
Spatial Analysis ◽  
Tumor Cells ◽  
Stromal Cells ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Tumor Associated Macrophages ◽  
Immune Infiltrate ◽  
Cellular Density

Immune infiltration is typically quantified using cellular density, not accounting for cellular clustering. Tumor-associated macrophages (TAM) activate oncogenic signaling through paracrine interactions with tumor cells, which may be better reflected by local cellular clustering than global density metrics. Using multiplex immunohistochemistry and digital pathologic analysis we quantified cellular density and cellular clustering for myeloid cell markers in 129 regions of interest from 55 samples from 35 patients with metastatic ccRCC. CD68+ cells were found to be clustered with tumor cells and dispersed from stromal cells, while CD163+ and CD206+ cells were found to be clustered with stromal cells and dispersed from tumor cells. CD68+ density was not associated with OS, while high tumor/CD68+ cell clustering was associated with significantly worse OS. These novel findings would not have been identified if immune infiltrate was assessed using cellular density alone, highlighting the importance of including spatial analysis in studies of immune cell infiltration of tumors. Significance: Increased clustering of CD68+ TAMs and tumor cells was associated with worse overall survival for patients with metastatic ccRCC. This effect would not have been identified if immune infiltrate was assessed using cell density alone, highlighting the importance of including spatial analysis in studies of immune cell infiltration of tumors.

scholarly journals Spatial Clustering of CD68+ Tumor Associated Macrophages with Tumor Cells is Associated with Worse Overall Survival in Metastatic Clear Cell Renal Cell Carcinoma

2021 ◽  
Author(s):  
Nicholas H Chakiryan ◽  
Gregory J Kimmel ◽  
Youngchul Kim ◽  
Ali Hajiran ◽  
Ahmet M Aydin ◽  
...  
Keyword(s):  
Overall Survival ◽  
Spatial Analysis ◽  
Tumor Cells ◽  
Stromal Cells ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Tumor Associated Macrophages ◽  
Immune Infiltrate ◽  
Cellular Density

ABSTRACTImmune infiltration is typically quantified using cellular density, not accounting for cellular clustering. Tumor-associated macrophages (TAM) activate oncogenic signaling through paracrine interactions with tumor cells, which may be better reflected by local cellular clustering than global density metrics. Using multiplex immunohistochemistry and digital pathologic analysis we quantified cellular density and cellular clustering for myeloid cell markers in 129 regions of interest from 55 samples from 35 patients with metastatic ccRCC. CD68+ cells were found to be clustered with tumor cells and dispersed from stromal cells, while CD163+ and CD206+ cells were found to be clustered with stromal cells and dispersed from tumor cells. CD68+ density was not associated with OS, while high tumor/CD68+ cell clustering was associated with significantly worse OS. These novel findings would not have been identified if immune infiltrate was assessed using cellular density alone, highlighting the importance of including spatial analysis in studies of immune cell infiltration of tumors.SIGNIFICANCEIncreased clustering of CD68+ TAMs and tumor cells was associated with worse overall survival for patients with metastatic ccRCC. This effect would not have been identified if immune infiltrate was assessed using cell density alone, highlighting the importance of including spatial analysis in studies of immune cell infiltration of tumors.

scholarly journals ARID1A Is a Prognostic Biomarker and Associated with Immune Infiltrates in Hepatocellular Carcinoma

2022 ◽  
Vol 2022 ◽  
pp. 1-14
Author(s):  
Yuanyuan Feng ◽  
Xinfang Tang ◽  
Changcheng Li ◽  
Ying Su ◽  
Xiaoyu Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Overall Survival ◽  
Immune Cell ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Cell Infiltration ◽  
Migration And Invasion ◽  
Risk Indicator ◽  
Immune Cell Infiltration

Objective. ARID1A has been discovered as a potential cancer biomarker. But its role in hepatocellular carcinoma (HCC) is subject to considerable dispute. Methods. The relationship between ARID1A and clinical factors was investigated. Clinicopathological variables related to overall survival in HCC subjects were identified using Cox and Kaplan–Meier studies. The connection between immune infiltrating cells and ARID1A expression was investigated using the tumor Genome Atlas (TCGA) dataset for gene set enrichment analysis (GSEA). Finally, a cell experiment was used to confirm it. Results. The gender and cancer topography (T) categorization of HCC were linked to increased ARID1A expression. Participants with advanced levels of ARID1A expression had a worse prognosis than someone with lower levels. ARID1A was shown to be a risk indicator of overall survival on its own. ARID1A expression is inversely proportional to immune cell infiltration. In vitro, decreasing ARID1A expression substantially slowed the cell cycle and decreased HCC cell proliferation, migration, and invasion. Conclusion. The expression of ARID1A could be used to predict the outcome of HCC. It is closely related to tumor immune cell infiltration.

RRx-001 is a phase III aerospace-derived small molecule that immunonormalizes the tumor microenvironment.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 156-156
Author(s):  
Pedro Cabrales
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Immune Cell ◽  
Cell Activity ◽  
Phase Iii ◽  
Cell Infiltration ◽  
Immune Checkpoints ◽  
Vascular Normalization ◽  
Tumor Associated Macrophages ◽  
Macrophage Phagocytosis

156 Background: Tumor associated macrophages (TAMs) with M2-like phenotypes produce angiogenic factors and cytokines which lead to vascular immaturity. M2 cytokines also impair immune cell activity. CD47 and SIRP⍺ are innate immune checkpoints which inhibit macrophage phagocytosis and enhance M2 polarization. Disruption of the CD47/SIRP⍺ axis polarize TAMs away from an M2-like phenotype to normalize tumor vessels and stimulate antitumor immunity. Normalized vessels facilitate delivery of drugs and immune cells and also sensitizes tumors to therapy and promotes M1-like TAM phenotype. RRx-001 modulates TAM infiltration and phenotype via CD47/SIRP⍺ downregulation, which normalizes both the tumor vasculature, and the immune cell milieu. Methods: The effect of RRx-001 on intratumoral blood flow was evaluated both preclinically and clinically with dynamic contrast MRI. An in vitro phagocytotic assay was used to determine whether RRx-001 promoted engulfment of A549 tumor cells by macrophages. Transcriptional mRNA profiling in murine tumor associated macrophages (TAMs) was performed to analyze the cytokine profile of TAMs in the presence or absence of RRx-001. Athymic mice with intracranial GBM43 were administered RRx-001 (10 mg/kg) followed 4 hours later by 0.4 mg of irinotecan by tail vein on days 12, 18, 24 and 30 after implantation of tumor cells. Mice were euthanized 24 hours after last irinotecan administration, with brains immediately resected and tumor tissue dissected prior to snap-freezing by immersion in liquid nitrogen. Results: RRx-001 was shown to induce: vascular normalization with increased intratumoral perfusion, dual downregulation of CD47 and SIRP⍺, increased phagocytosis, improved delivery of chemotherapy and increased T cell infiltration. Conclusions: RRx-001 leads to vascular normalization and enhanced delivery of chemotherapy and immune cell infiltration. The increase in tumor perfusion diminishes hypoxia and also serves to polarize TAMs away from an M2-like state. These results also suggest and are borne out by clinical biopsies that the effect of RRx-001 depends on the number of TAMs present in the tumor microenvironment with higher numbers leading to better activity.

scholarly journals SEC61G Overexpression and DNA Amplification Correlates With Prognosis and Immune Cell Infiltration in Head and Neck Squamous Cell Carcinoma

2021 ◽  
Author(s):  
Tianzhu Lu ◽  
Yiping Chen ◽  
Xiaochang Gong ◽  
Qiaojuan Guo ◽  
Canyang Lin ◽  
...  
Keyword(s):  
Overall Survival ◽  
Squamous Cell Carcinoma ◽  
T Cell ◽  
Prognostic Factor ◽  
Immune Cell ◽  
Dna Amplification ◽  
Independent Prognostic Factor ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Disease Prognosis

Abstract BackgroundThe SEC61 translocon gamma subunit (SEC61G) is a component of the SEC61 complex, which import protein into the endoplasmic reticulum. However, the correlation between SEC61G and disease prognosis in head and neck squamous cell carcinoma (HNSCC) remains unclear. MethodsSEC61G expression was analyzed using publicly-available datasets. The association between SEC61G and disease prognosis was evaluated. SEC61G methylation and copy number variation were investigated and gene set enrichment analysis (GSEA) and gene ontology (GO) analyses identified SEC61G-associated functions. We also investigated the correlation between SEC61G and immune cell infiltration. Finally, immunohistochemistry (IHC) was used to detect SEC61G expression in oropharyngeal carcinoma. ResultsSEC61G was overexpressed in pan-cancers, including HNSCC, and negatively correlated with overall survival (p<0.001 for TCGA-HNSCC and p=0.019 for GSE65858). Moreover, SEC61G was an independent prognostic factor for overall survival (OS) in TCGA and GSE65858 [hazard ratio (HR)=1.80, 95% CI: 1.35-2.39, p<0.001; HR＝1.87, 95% CI: 1.14-3.07, p=0.013, respectively). SEC61G DNA amplification (9.66% of patients) was significantly associated with poor OS (p=0.034). SEC61G overexpression and DNA amplification negatively correlated with B cell, CD8+ T cell, CD4+ T cell, macrophage, neutrophil, and dendritic cell infiltration (all p<0.05). Among patients with metastatic urothelial cancer received atezolizumab, patients with high SEC61G expression had an inferior OS (p=0.006). Furthermore, SEC61G protein expression was also an independent prognostic factor of OS (HR=2.49, 95% CI: 1.15-5.30, p=0.020) and progression-free survival (HR=2.82, 95% CI: 1.36-5.84, p=0.005) for oropharyngeal cancer. ConclusionsSEC61G is overexpressed in HNSCC and is an independent prognostic factor for OS. SEC61G DNA amplification contributes to overexpression and poor outcome. Interestingly, SEC61G correlates with immune cell infiltration in HNSCC. These findings suggest that SEC61G is a potential broad-spectrum biomarker for prognosis in HNSCC.

scholarly journals Identification of Clinical and Tumor Microenvironment Characteristics of Hypoxia-Related Risk Signature in Lung Adenocarcinoma

2021 ◽  
Vol 8 ◽  
Author(s):  
Zili Dai ◽  
Taisheng Liu ◽  
Guihong Liu ◽  
Zhen Deng ◽  
Peng Yu ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Tumor Microenvironment ◽  
Lung Adenocarcinoma ◽  
Immune Cell ◽  
Risk Group ◽  
High Risk Group ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Related Risk

Background: Lung cancer is the leading cause of cancer-related death globally. Hypoxia can suppress the activation of the tumor microenvironment (TME), which contributes to distant metastasis. However, the role of hypoxia-mediated TME in predicting the diagnosis and prognosis of lung adenocarcinoma (LUAD) patients remains unclear.Methods: Both RNA and clinical data from the LUAD cohort were downloaded from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Both univariate and multivariate Cox regression analyses were used to further screen prognosis-related hypoxia gene clusters. Time-dependent receiver operation characteristic (ROC) curves were established to evaluate the predictive sensitivity and specificity of the hypoxia-related risk signature. The characterization of gene set enrichment analysis (GSEA) and TME immune cell infiltration were further explored to identify hypoxia-related immune infiltration.Results: Eight hypoxia-related genes (LDHA, DCN, PGK1, PFKP, FBP1, LOX, ENO3, and CXCR4) were identified and established to construct a hypoxia-related risk signature. The high-risk group showed a poor overall survival compared to that of the low-risk group in the TCGA and GSE68465 cohorts (p &lt; 0.0001). The AUCs for 1-, 3-, and 5-year overall survival were 0.736 vs. 0.741, 0.656 vs. 0.737, and 0.628 vs. 0.649, respectively. The high-risk group was associated with immunosuppression in the TME.Conclusion: The hypoxia-related risk signature may represent an independent biomarker that can differentiate the characteristics of TME immune cell infiltration and predict the prognosis of LUAD.

scholarly journals Association of Galectin 9 Expression with Immune Cell Infiltration, Programmed Cell Death Ligand-1 Expression, and Patient’s Clinical Outcome in Triple-Negative Breast Cancer

Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1383
Author(s):  
Mi-Ha Ju ◽  
Kyung-Do Byun ◽  
Eun-Hwa Park ◽  
Jin-Hwa Lee ◽  
Song-Hee Han
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Clinical Outcome ◽  
Tumor Cells ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Immune Cell Infiltration

Galectin-9 (Gal-9) is an immune checkpoint protein that facilitates T cell exhaustion and modulates the tumor-associated microenvironment, and could be a potential target for immune checkpoint inhibition. This study was conducted to assess Gal-9 expression in triple-negative breast cancer (TNBC) and evaluate its association with programmed cell death ligand 1 (PD-L1) expression and immune cell infiltration in tumors and the clinical outcome of patients. Overall, 109 patients with TNBC were included. Gal-9 expression was assessed its relationships with tumor clinicopathologic characteristics, tumor-infiltrating lymphocyte (TIL) levels, PD-L1+ immune cells, and tumor cells by tissue microarray and immunohistochemistry. Low Gal-9 expression was statistically correlated with higher tumor stage (p = 0.031) and presence of lymphovascular invasion (p = 0.008). High Gal-9 expression was associated with a high level of stromal TILs (sTIL; p = 0.011) and positive PD-L1 expression on tumor cells (p = 0.004). In survival analyses, low Gal-9 expression was associated with significantly poor OS (p = 0.013) in patients with TNBC with PD-L1 negativity in tumor cells. Our findings suggest that increased Gal-9 expression is associated with changes in the antitumor microenvironment, such as increased immune cell infiltration and antimetastatic changes. This study emphasizes the predictive value and promising clinical applications of Gal-9 in TNBC.

Identification of the immune cell infiltration landscape in pancreatic cancer to assist immunotherapy

2021 ◽  
Author(s):  
Zizheng Wang ◽  
Wenbo Zou ◽  
Fei Wang ◽  
Gong Zhang ◽  
Kuang Chen ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Overall Survival ◽  
Survival Analysis ◽  
Patient Outcomes ◽  
Clustering Algorithm ◽  
Immune Cell ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Cell Infiltration ◽  
Immune Cell Infiltration

Background: A malignant tumor's immune environment, including infiltrating immune cell status, can be critical to patient outcomes. Recent studies have shown that immune cell infiltration (ICI) in pancreatic cancer (PC) is highly correlated with the response to immunotherapy and patient prognosis. Therefore, we aimed to create an ICI score that accurately predicts patient outcomes and immunotherapeutic efficacy. Methods: The ICI statuses of patients with PC were estimated from the publicly available The Cancer Genome Atlas (TCGA) pancreatic ductal adenocarcinoma and GSE57495 gene expression datasets using two computational algorithms (CIBERSORT and ESTIMATE). ICI and transcriptome subsets were defined using a clustering algorithm, and survival analysis was also performed. Principal component analysis was used to calculate the novel ICI score, and gene set enrichment analysis was performed to identify the pathways underlying the defined clusters. The tumor mutational burden (TMB) was further explored in TCGA cohort, and survival analysis was used to assess the capability of the ICI and TMB scores to predict overall survival. Additionally, common driver gene mutations and their differential expression in the different ICI score group were investigated. Results: The ICI landscapes of 240 patients were generated using the devised algorithm, revealing three ICI and three gene clusters whose use improved the prediction of overall survival (p = 0.019 and p < 0.001, respectively). Crucial immune checkpoint genes were differentially expressed among these subtypes; the RIG-I-LIKE and NOD-LIKE receptor signaling pathways were enriched in samples with low ICI scores (p < 0.05). We also found that the TMB scores could predict survival outcomes, whereas the ICI scores also could predict prognoses independent of TMB. Notably, ICI scores could effectively predict responses to immunotherapy. KRAS, TP53, CDKN2A, SMAD4 and TTN remained the most commonly mutated genes in PC; moreover, KRAS and TP53 mutation rates were significantly different between the two ICI score groups. Conclusions: We developed a novel ICI score that could independently predict the response to immunotherapy and survival of patients with PC. Evaluation of the ICI landscape in a larger cohort could clarify the interactions between these infiltrating cells, the tumor microenvironment and response to immunotherapy.

scholarly journals Comprehensive analysis identifies IFI16 as a novel signature associated with overall survival and immune infiltration of skin cutaneous melanoma

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Hanwen Wang ◽  
Xiaoxia Xie ◽  
Junyou Zhu ◽  
Shaohai Qi ◽  
Julin Xie
Keyword(s):  
Overall Survival ◽  
Cutaneous Melanoma ◽  
Immune Cell ◽  
Normal Skin ◽  
Critical Role ◽  
Comprehensive Analysis ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Discriminatory Ability ◽  
Immune Infiltration

Abstract Background Skin cutaneous melanoma (SKCM) is the most common skin tumor with high mortality. The unfavorable outcome of SKCM urges the discovery of prognostic biomarkers for accurate therapy. The present study aimed to explore novel prognosis-related signatures of SKCM and determine the significance of immune cell infiltration in this pathology. Methods Four gene expression profiles (GSE130244, GSE3189, GSE7553 and GSE46517) of SKCM and normal skin samples were retrieved from the GEO database. Differentially expressed genes (DEGs) were then screened, and the feature genes were identified by the LASSO regression and Boruta algorithm. Survival analysis was performed to filter the potential prognostic signature, and GEPIA was used for preliminary validation. The area under the receiver operating characteristic curve (AUC) was obtained to evaluate discriminatory ability. The Gene Set Variation Analysis (GSVA) was performed, and the composition of the immune cell infiltration in SKCM was estimated using CIBERSORT. At last, paraffin-embedded specimens of primary SKCM and normal skin tissues were collected, and the signature was validated by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). Results Totally 823 DEGs and 16 feature genes were screened. IFI16 was identified as the signature associated with overall survival of SKCM with a great discriminatory ability (AUC > 0.9 for all datasets). GSVA noticed that IFI16 might be involved in apoptosis and ultraviolet response in SKCM, and immune cell infiltration of IFI16 was evaluated. At last, FISH and IHC both validated the differential expression of IFI16 in SKCM. Conclusions In conclusion, our comprehensive analysis identified IFI16 as a signature associated with overall survival and immune infiltration of SKCM, which may play a critical role in the occurrence and development of SKCM.

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