ERAP2 Is Associated With Immune Infiltration and Predicts Favorable Prognosis in SqCLC

BackgroundImmunotherapy has been proven effective among several human cancer types, including Squamous cell lung carcinoma (SqCLC). ERAP2 plays a pivotal role in peptide trimming of many immunological processes. However, the prognostic role of ERAP2 and its relationship with immune cell infiltration in SqCLC remains unclear.MethodsThe differential expression of ERAP2 was identified via GEO and TCGA databases. We calculated the impact of ERAP2 on clinical prognosis using the Kaplan-Meier plotter. TIMER was applied to evaluate the abundance of immune cells infiltration and immune markers. SqCLC tissue microarrays containing 190 patients were constructed, and we performed immunohistochemical staining for ERAP2, CD8, CD47, CD68, and PD-L1 to validate our findings in public data.ResultsIn the GEO SqCLC database, ERAP2 was upregulated in patients with better survival (p=0.001). ERAP2 expression in SqCLC was significantly lower than that of matched normal samples (p<0.05) based on TCGA SqCLC data. Higher expression of ERAP2 was significantly associated with better survival in SqCLC patients from TCGA (p=0.007), KM-plotter (p=0.017), and our tissue microarrays (TMAs) (p=0.026). In univariate and multivariate Cox analysis of SqCLC TMAs, high ERAP2 expression was identified as an independent protective factor for SqCLC patients (Univariate Cox, HR=0.659, range 0.454-0.956, p<0.05. Multivariate Cox, HR=0.578, range 0.385-0.866, p<0.05). In TIMER, ERAP2 was positively correlated with several immune markers (CD274, p=1.27E-04; CD68, p=5.88E-08) and immune infiltrating cells (CD8+ T cell, p=4.09E-03; NK cell, p=1.00E-04). In our cohort, ERAP2 was significantly correlated with CD8+ tumor-infiltrating lymphocytes (TILs) (p=0.0029), and patients with higher ERAP2 expression had a higher percentage of PD-L1 positive patients (p=0.049) and a higher CD8+ TILs level (p=0.036).ConclusionsFor the first time, our study demonstrates that higher expression of ERAP2 is tightly associated with the immuno-supportive microenvironment and can predict a favorable prognosis in SqCLC. Meanwhile, ERAP2 may be a promising immunotherapeutic target for patients with SqCLC.

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Correlation analysis of RDM1 gene with immune infiltration and clinical prognosis of hepatocellular carcinoma

Bioscience Reports ◽

10.1042/bsr20203978 ◽

2021 ◽

Vol 41 (9) ◽

Author(s):

Chen Qiu ◽

Zuyin Li ◽

Wanyue Cao ◽

Xiaoni Cai ◽

Li Ye ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Mrna Expression ◽

Messenger Rna ◽

Immune Cell ◽

Liver Tumors ◽

Progression Free Survival ◽

Marker Genes ◽

Clinical Prognosis ◽

Immune Infiltration ◽

The Impact

Abstract Purpose: Liver hepatocellular carcinoma (LIHC) is one of the most common primary malignant liver tumors worldwide. The RAD52 motif-containing protein 1 (RDM1) has been shown to play a role in mediating DNA damage repair and homologous recombination. The present study was designed to determine the expression of RDM1 and its prognostic value as well as its relationship with immune infiltration in LIHC patients. Methods: Oncomine and Tumor Immunoassay Resource were used to assess the expression of RDM1. PrognoScan and Kaplan–Meier bioinformatics database were used to analyze the impact of clinical influencing factors on prognosis. Finally, the Tumor Immune Assessment Resource (TIMER) and Gene Expression Analysis Interactive Analysis (GEPIA) databases were used to detect the correlation between the expression of RDM1 and expression of marker genes related to immune infiltration. Immunohistochemistry (IHC) method was used to detect the expression level of RDM1 in 90 cases of hepatocellular carcinoma and adjacent normal liver tissues. Results: RDM1 expression was up-regulated in most cancers. The expression of RDM1 was remarkably higher than that of the corresponding normal control genes in LIHC tissues. The increase in RDM1 messenger RNA (mRNA) expression was closely related to the decreases in overall survival (OS) and progression-free survival (PFS). Additionally, the increase in RDM1 mRNA expression was closely related to the infiltration levels of macrophages, CD8+ T cells and B cells and was positively correlated with a variety of immune markers in LIHC. Conclusion: The findings of the present study demonstrate that RDM1 is a potentially valuable prognostic biomarker that can help determine the progression of cancer and is associated with immune cell infiltration in LIHC.

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Intratumoral immune reaction: A novel paradigm for cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.4_suppl.471 ◽

2011 ◽

Vol 29 (4_suppl) ◽

pp. 471-471 ◽

Cited By ~ 1

Author(s):

J. Galon ◽

B. Mlecnik ◽

A. Kirilovsky ◽

G. Bindea ◽

M. Tosolini ◽

...

Keyword(s):

Colorectal Cancer ◽

T Cells ◽

Cancer Patients ◽

Immune Reaction ◽

Immune Cell ◽

Human Cancer ◽

Effector Memory ◽

Tumor Escape ◽

Primary Tumors ◽

The Impact

471 Background: To date the anatomic extent of tumor (TNM classifications) has been by far the most important factors to predict the prognosis of cancer patients. However, the impact of immune responses and tumor escape on patient prognosis in human cancer is poorly understood. Methods: We analyzed large retrospective cohorts of colorectal cancer patients. Results: We showed that tumors from human colorectal cancer with a high density of infiltrating memory and effector memory T-cells (T-EM) are less likely to disseminate to lymphovascular and perineural structures and to regional lymph-nodes (New Engl J Med, 2005). We showed that the combination of immune parameters associating the nature, the density, the functional orientation and the location of immune cells within the tumor was essential to accurately define the impact of the local host immune reaction on patients prognosis (Science, 2006). We proposed to define these immune criteria as “immune contexture.” Analysis of patients with early-stage colorectal cancer confirmed the major role of cyotoxic effector T cells in predicting the prognosis of the patients (J Clin Oncol, 2009). Investigation of the primary tumor microenvironment allowed us to uncover the association of favorable outcomes with efficient coordination of the intratumoral immune response. We described four major immune coordination profiles within primary tumors depending on the balance between tumor escape and immune coordination. Recent advances analyzing mechanisms responsible for lymphocytic infiltration will be discussed. Conclusions: The density and the immune-cell location within the tumor have a prognostic value that is superior of those of the TNM classifications. Tumor invasion is statistically dependent on the host-immune reaction. No significant financial relationships to disclose.

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CancerImmunityQTL: a database to systematically evaluate the impact of genetic variants on immune infiltration in human cancer

Nucleic Acids Research ◽

10.1093/nar/gkaa805 ◽

2020 ◽

Vol 49 (D1) ◽

pp. D1065-D1073

Author(s):

Jianbo Tian ◽

Yimin Cai ◽

Yue Li ◽

Zequn Lu ◽

Jinyu Huang ◽

...

Keyword(s):

Immune Cells ◽

Genetic Variants ◽

Immune Cell ◽

Human Cancer ◽

Tumor Development ◽

Multiple Cancer ◽

Immune Infiltration ◽

Cancer Types ◽

Cell Fractions ◽

The Impact

Abstract Tumor-infiltrating immune cells as integral component of the tumor microenvironment are associated with tumor progress, prognosis and responses to immunotherapy. Genetic variants have been demonstrated to impact tumor-infiltrating, underscoring the heritable character of immune landscape. Therefore, identification of immunity quantitative trait loci (immunQTLs), which evaluate the effect of genetic variants on immune cells infiltration, might present a critical step toward fully understanding the contribution of genetic variants in tumor development. Although emerging studies have demonstrated the determinants of germline variants on immune infiltration, no database has yet been developed to systematically analyze immunQTLs across multiple cancer types. Using genotype data from TCGA database and immune cell fractions estimated by CIBERSORT, we developed a computational pipeline to identify immunQTLs in 33 cancer types. A total of 913 immunQTLs across different cancer types were identified. Among them, 5 immunQTLs are associated with patient overall survival. Furthermore, by integrating immunQTLs with GWAS data, we identified 527 immunQTLs overlapping with known GWAS linkage disequilibrium regions. Finally, we constructed a user-friendly database, CancerImmunityQTL (http://www.cancerimmunityqtl-hust.com/) for users to browse, search and download data of interest. This database provides an informative resource to understand the germline determinants of immune infiltration in human cancer and benefit from personalized cancer immunotherapy.

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The Immune Landscape of Colorectal Cancer

Cancers ◽

10.3390/cancers13215545 ◽

2021 ◽

Vol 13 (21) ◽

pp. 5545

Author(s):

Artur Mezheyeuski ◽

Patrick Micke ◽

Alfonso Martín-Bernabé ◽

Max Backman ◽

Ina Hrynchyk ◽

...

Keyword(s):

Colorectal Cancer ◽

Immune Cell ◽

Clinical Importance ◽

Tissue Microarrays ◽

Cell Types ◽

T Cell Subsets ◽

M2 Macrophages ◽

Cd8 Cells ◽

The Impact

While the clinical importance of CD8+ and CD3+ cells in colorectal cancer (CRC) is well established, the impact of other immune cell subsets is less well described. We sought to provide a detailed overview of the immune landscape of CRC in the largest study to date in terms of patient numbers and in situ analyzed immune cell types. Tissue microarrays from 536 patients were stained using multiplexed immunofluorescence panels, and fifteen immune cell subclasses, representing adaptive and innate immunity, were analyzed. Overall, therapy-naïve CRC patients clustered into an ‘inflamed’ and a ‘desert’ group. Most T cell subsets and M2 macrophages were enriched in the right colon (p-values 0.046–0.004), while pDC cells were in the rectum (p = 0.008). Elderly patients had higher infiltration of M2 macrophages (p = 0.024). CD8+ cells were linked to improved survival in colon cancer stages I-III (q = 0.014), while CD4+ cells had the strongest impact on overall survival in metastatic CRC (q = 0.031). Finally, we demonstrated repopulation of the immune infiltrate in rectal tumors post radiation, following an initial radiation-induced depletion. This study provides a detailed analysis of the in situ immune landscape of CRC paving the way for better diagnostics and providing hints to better target the immune microenvironment.

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Impact of Work and Recreational Physical Activity on Prediabetes Condition among U.S. Adults: NHANES 2015–2016

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18041378 ◽

2021 ◽

Vol 18 (4) ◽

pp. 1378

Author(s):

Lenin Pazmino ◽

Wilmer Esparza ◽

Arian Ramón Aladro-Gonzalvo ◽

Edgar León

Keyword(s):

Physical Activity ◽

Protective Factor ◽

Hemoglobin A1c ◽

Physical Activities ◽

Recreational Physical Activity ◽

Physically Active ◽

Hba1c Test ◽

Health And Nutrition ◽

The Impact

More minutes of physical activity (PA) accumulated during a day are associated with a lower risk of diabetes mellitus type 2. However, it is less known if distinct dimensions of PA can produce a different protective effect in the prevention of prediabetes. The aim of this study was to analyze the impact of work and recreational PA on prediabetes among U.S. adults during the period 2015–2016 using the National Health and Nutrition Examination Survey (NHANES) database. Individuals (n = 4481) with hemoglobin A1c (HbA1c) test values of 5.7% to 6.4% were included. A logistic regression multivariate-adjusted analysis was conducted to estimate the association between the odds ratios (ORs) and 95% confidence intervals (CIs) of prediabetes, with work and recreational PA. The prevalence of prediabetes among U.S. adults was lower in physically active individuals both at work (~24%) and recreational (~21%) physical activities compared to individuals who were not physically active (27 to 30%). Individuals lacking practice of recreational PA had a high risk of prediabetes (OR = 1.26, 95% CI: 1.080 to 1.466). PA may be a protective factor for prediabetes conditions depending on gender, age, ethnic group, waist circumference, and thyroid disease.

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Oxidative Stress Compromises Lymphocyte Function in Neonatal Dairy Calves

Antioxidants ◽

10.3390/antiox10020255 ◽

2021 ◽

Vol 10 (2) ◽

pp. 255

Author(s):

Wilmer Cuervo ◽

Lorraine M. Sordillo ◽

Angel Abuelo

Keyword(s):

Oxidative Stress ◽

Immune Responses ◽

Immune Cell ◽

Lymphocyte Activation ◽

Dairy Calves ◽

Lymphocyte Function ◽

Newborn Calves ◽

Ifn Γ ◽

The Impact

Dairy calves are unable to mount an effective immune response during their first weeks of life, which contributes to increased disease susceptibility during this period. Oxidative stress (OS) diminishes the immune cell capabilities of humans and adult cows, and dairy calves also experience OS during their first month of life. However, the impact that OS may have on neonatal calf immunity remains unexplored. Thus, we aimed to evaluate the impact of OS on newborn calf lymphocyte functions. For this, we conducted two experiments. First, we assessed the association of OS status throughout the first month of age and the circulating concentrations of the cytokines interferon-gamma (IFN-γ) and interleukin (IL) 4, as well as the expression of cytokine-encoding genes IFNG, IL2, IL4, and IL10 in peripheral mononuclear blood cells (PBMCs) of 12 calves. Subsequently, we isolated PBMCs from another 6 neonatal calves to investigate in vitro the effect of OS on immune responses in terms of activation of lymphocytes, cytokine expression, and antibody production following stimulation with phorbol 12-myristate 13-acetate or bovine herpesvirus-1. The results were compared statistically through mixed models. Calves exposed to high OS status in their first month of age showed higher concentrations of IL-4 and expression of IL4 and IL10 and lower concentrations of IFN-γ and expression of IFNG and IL2 than calves exposed to lower OS. In vitro, OS reduced lymphocyte activation, production of antibodies, and protein and gene expression of key cytokines. Collectively, our results demonstrate that OS can compromise some immune responses of newborn calves. Hence, further studies are needed to explore the mechanisms of how OS affects the different lymphocyte subsets and the potential of ameliorating OS in newborn calves as a strategy to augment the functional capacity of calf immune cells, as well as enhance calves’ resistance to infections.

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High Expression of KLF10 Is Associated with Favorable Survival in Patients with Oral Squamous Cell Carcinoma

Medicina ◽

10.3390/medicina57010017 ◽

2020 ◽

Vol 57 (1) ◽

pp. 17

Author(s):

Chung-Min Yeh ◽

Yi-Ju Lee ◽

Po-Yun Ko ◽

Yueh-Min Lin ◽

Wen-Wei Sung

Keyword(s):

Survival Rate ◽

Oral Cancer ◽

Cancer Patients ◽

Protective Factor ◽

Female Gender ◽

Vital Role ◽

Cancer Stage ◽

Independent Prognostic Marker ◽

Oral Cancer Patients ◽

The Impact

Background and objectives: Krüppel-like transcription factor 10 (KLF10) plays a vital role in regulating cell proliferation, including the anti-proliferative process, activation of apoptosis, and differentiation control. KLF10 may also act as a protective factor against oral cancer. We studied the impact of KLF10 expression on the clinical outcomes of oral cancer patients to identify its role as a prognostic factor in oral cancer. Materials and Methods: KLF10 immunoreactivity was analyzed by immunohistochemical (IHC) stain analysis in 286 cancer specimens from primary oral cancer patients. The prognostic value of KLF10 on overall survival was determined by Kaplan–Meier analysis and the Cox proportional hazard model. Results: High KLF10 expression was significantly associated with male gender and betel quid chewing. The 5-year survival rate was greater for patients with high KLF10 expression than for those with low KLF10 expression (62.5% vs. 51.3%, respectively; p = 0.005), and multivariate analyses showed that high KLF10 expression was the only independent factor correlated with greater overall patient survival. The significant correlation between high KLF10 expression and a higher 5-year survival rate was observed in certain subgroups of clinical parameters, including female gender, non-smokers, cancer stage T1, and cancer stage N0. Conclusions: KLF10 expression, detected by IHC staining, could be an independent prognostic marker for oral cancer patients.

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Multi-institutional TSA-amplified Multiplexed Immunofluorescence Reproducibility Evaluation (MITRE) Study

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-002197 ◽

2021 ◽

Vol 9 (7) ◽

pp. e002197

Author(s):

Janis M Taube ◽

Kristin Roman ◽

Elizabeth L Engle ◽

Chichung Wang ◽

Carmen Ballesteros-Merino ◽

...

Keyword(s):

Breast Carcinoma ◽

Multispectral Imaging ◽

Immune Cell ◽

Clinical Laboratory ◽

Predictive Biomarkers ◽

Spatial Arrangement ◽

Tissue Microarrays ◽

Fluorescent Detection ◽

Nsclc Tissue ◽

Tissue Sections

BackgroundEmerging data suggest predictive biomarkers based on the spatial arrangement of cells or coexpression patterns in tissue sections will play an important role in precision immuno-oncology. Multiplexed immunofluorescence (mIF) is ideally suited to such assessments. Standardization and validation of an end-to-end workflow that supports multisite trials and clinical laboratory processes are vital. Six institutions collaborated to: (1) optimize an automated six-plex assay focused on the PD-1/PD-L1 axis, (2) assess intersite and intrasite reproducibility of staining using a locked down image analysis algorithm to measure tumor cell and immune cell (IC) subset densities, %PD-L1 expression on tumor cells (TCs) and ICs, and PD-1/PD-L1 proximity assessments.MethodsA six-plex mIF panel (PD-L1, PD-1, CD8, CD68, FOXP3, and CK) was rigorously optimized as determined by quantitative equivalence to immunohistochemistry (IHC) chromogenic assays. Serial sections from tonsil and breast carcinoma and non-small cell lung cancer (NSCLC) tissue microarrays (TMAs), TSA-Opal fluorescent detection reagents, and antibodies were distributed to the six sites equipped with a Leica Bond Rx autostainer and a Vectra Polaris multispectral imaging platform. Tissue sections were stained and imaged at each site and delivered to a single site for analysis. Intersite and intrasite reproducibility were assessed by linear fits to plots of cell densities, including %PDL1 expression by TCs and ICs in the breast and NSCLC TMAs.ResultsComparison of the percent positive cells for each marker between mIF and IHC revealed that enhanced amplification in the mIF assay was required to detect low-level expression of PD-1, PD-L1, FoxP3 and CD68. Following optimization, an average equivalence of 90% was achieved between mIF and IHC across all six assay markers. Intersite and intrasite cell density assessments showed an average concordance of R2=0.75 (slope=0.92) and R2=0.88 (slope=0.93) for breast carcinoma, respectively, and an average concordance of R2=0.72 (slope=0.86) and R2=0.81 (slope=0.68) for NSCLC. Intersite concordance for %PD-L1+ICs had an average R2 value of 0.88 and slope of 0.92. Assessments of PD-1/PD-L1 proximity also showed strong concordance (R2=0.82; slope=0.75).ConclusionsAssay optimization yielded highly sensitive, reproducible mIF characterization of the PD-1/PD-L1 axis across multiple sites. High concordance was observed across sites for measures of density of specific IC subsets, measures of coexpression and proximity with single-cell resolution.

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Clinicopathological features of Egyptian colorectal cancer patients regarding somatic genetic mutations especially in KRAS gene and microsatellite instability status: a pilot study

Egyptian Journal of Medical Human Genetics ◽

10.1186/s43042-019-0028-z ◽

2019 ◽

Vol 20 (1) ◽

Author(s):

Neemat M. Kassem ◽

Gamal Emera ◽

Hebatallah A. Kassem ◽

Nashwa Medhat ◽

Basant Nagdy ◽

...

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Cpg Island ◽

Human Cancer ◽

Statistical Significance ◽

Public Health Problem ◽

World Health ◽

Cpg Island Methylator Phenotype ◽

Number Of Patients ◽

The Impact

Abstract Background Colorectal cancer (CRC) is the third most common cause of cancer-related deaths which contributes to a significant public health problem worldwide with 1.8 million new cases and almost 861,000 deaths in 2018 according to the World Health Organization. It exhibits 7.4% of all diagnosed cancer cases in the region of the Middle East and North Africa. Molecular changes that happen in CRCs are chromosomal instability, microsatellite instability (MSI), and CpG island methylator phenotype. The human RAS family (KRAS, NRAS, and HRAS) is the most frequently mutated oncogenes in human cancer appearing in 45% of colon cancers. Determining MSI status across CRCs offers the opportunity to identify patients who are likely to respond to targeted therapies such as anti-PD-1. Therefore, a method to efficiently determine MSI status for every cancer patient is needed. Results KRAS mutations were detected in 31.6% of CRC patients, namely in older patients (p = 0.003). Codons 12 and 13 constituted 5/6 (83.3%) and 1/6 (16.7%) of all KRAS mutations, respectively. We found three mutations G12D, G12C, and G13D which occur as a result of substitution at c.35G>A, c.34G>T, and c.38G>A and have been detected in 4/6 (66.6%), 1/6 (16.7%), and 1/6 (16.7%) patients, respectively. Eleven (57.9%) patients had microsatellite instability-high (MSI-H) CRC. A higher percentage of MSI-H CRC was detected in female patients (p = 0.048). Eight patients had both MSI-H CRC and wild KRAS mutation with no statistical significance was found between MSI status and KRAS mutation in these studied patients. Conclusion In conclusion, considering that KRAS mutations confer resistance to EGFR inhibitors, patients who have CRC with KRAS mutation could receive more tailored management by defining MSI status. MSI-high patients have enhanced responsiveness to anti-PD-1 therapies. Thus, the question arises as to whether it is worth investigating this association in the routine clinical setting or not. Further studies with a larger number of patients are needed to assess the impact of MSI status on Egyptian CRC care.

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669 Increased Nightmares During the COVID-19 Pandemic: Exploring the Role of Resilience and Emotions

SLEEP ◽

10.1093/sleep/zsab072.667 ◽

2021 ◽

Vol 44 (Supplement_2) ◽

pp. A261-A262

Author(s):

Jérémie Potvin ◽

Laura Ramos Socarras ◽

Geneviève Forest

Keyword(s):

Young Adults ◽

Protective Factor ◽

Negative Emotions ◽

Unique Contribution ◽

Health Issues ◽

Resilience Scale ◽

And Gender ◽

The Impact ◽

Tremendous Impact

Abstract Introduction COVID-19 had a tremendous impact on many aspects of our lives and has caused an increase in stress and mental health issues in many people. We have recently found that there was an increase in nightmares during the pandemic in young adults. Since emotions have been associated with both resilience and nightmares, the objective of this study was to investigate the role of resilience and emotional changes in the increase in nightmares observed during the pandemic, in a group of young adults. Methods Resilience, emotions and nightmares were assessed using the Connor-Davidson Resilience Scale-10, the Differential Emotions Scale-IV and an adapted version of the Pittsburgh Sleep Quality Index. Measures were administered to 209 young adults (18–25 years old, 76.1% females). Hierarchical multiple regression models were computed to examine the unique contribution of changes in positive and negative emotions during the pandemic to the increase in nightmares during the pandemic. Analyses were controlled for nightmares and emotions prior to COVID-19, and for gender. The sample was separated in two groups: resilient and less resilient young adults. Results Results show that in less resilient young adults, nightmares prior to COVID-19 (β=.79, p<.001) and increase in negative emotions (β=.21, p=.033) significantly predicted nightmares during the pandemic and explained 67.0% of their variance. In resilient young adults, nightmares prior to COVID-19 (β=.56, p<.001) and gender (β=-.15, p=.04) significantly predicted nightmares during the pandemic and explained 52.0% of the variance. Conclusion Our results show that increase in negative emotions during the pandemic is associated with an increase in nightmares in less resilient young adults, but not in resilient young adults. Furthermore, our results show that in resilient young adults, being a woman is associated with an increase in nightmares during the pandemic. These results suggest that resilience may be a protective factor in managing the impact of negative emotions on nightmares, but only in men. Support (if any):

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