scholarly journals P03.15 Site-specific immune evasion and substantial heterogeneity within entities provide evidence for personalized immunotherapy

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A28-A29
Author(s):  
M Thelen ◽  
K Wennhold ◽  
J Lehmann ◽  
E Staib ◽  
MA Garcia Marquez ◽  
...  
Keyword(s):  
T Cells ◽  
Antigen Presentation ◽  
Immune Evasion ◽  
Immune Cell ◽  
Immune Escape ◽  
Immune Cell Infiltration ◽  
Site Specific ◽  
Immune Escape Mechanisms ◽  
Substantial Heterogeneity ◽  
Research Grant

BackgroundImmune-checkpoint inhibition (CKI) demonstrated remarkable therapeutic efficacy in several kinds of cancer. However, immune escape mechanisms lead to primary or secondary resistance in the majority of patients. Most predictive biomarkers failed, as the primary target of CKI is not the tumor cell itself, but the crosstalk between immune- and cancer cells. We aimed to characterize the immune evasion landscape in primary tumors across different entities.Materials and MethodsExpression of 32 immune-regulatory molecules on lymphocytes was analyzed in peripheral blood and tumor infiltrating lymphocytes (TILs) of 146 primary tumor patients across 10 different entities using flow cytometry. NanoString was applied to determine RNA expression of the respective ligands and 20 genes associated with antigen presentation. Expression of coinhibitory ligands on tumor cells was assessed by immunohistochemistry. To quantify the immune cell infiltration, digital pathology was used and the Immunoscore was generated for each patient.ResultsWhile an increase of regulatory T cells was a common feature across all entities, we found site-specific differences regarding other lymphocyte subsets and expression of immune-regulatory molecules by TILs and tumor cells. Expression of co-inhibitory molecules on tumor infiltrating T cells accumulated especially in advanced stage cancers whereas immune cell infiltration was mainly associated with enhanced antigen presentation. Co-expression of multiple immune-inhibitory ligands was most frequent in colorectal, lung and ovarian carcinoma. Genes related to antigen presentation were frequently dysregulated in seminoma, liver and lung cancer.ConclusionsImmune evasion is a common feature of cancer and frequently detected co-occurrence of multiple mechanisms probably contributes to resistance against immunotherapy. We describe substantial heterogeneity regarding immune escape mechanisms between patients with the same primary tumor. Individualized immunotherapeutic strategies based on pretherapeutic evaluation of the immune evasion landscape might help to improve response to CKI.Disclosure InformationM. Thelen: None. K. Wennhold: None. J. Lehmann: None. E. Staib: None. M.A. Garcia Marquez: None. P. Lohneis: None. A. Lechner: None. S. Wagener-Ryczek: None. P.S. Plum: None. D. Pfister: None. F. Dörr: None. D. Beutner: None. F. Thangarajah: None. D. Ratiu: None. W. Malter: None. S. Merkelbach-Bruse: None. C.J. Bruns: None. A. Quaas: None. M.S. von Bergwelt-Baildon: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Significant; Astellas. F. Consultant/Advisory Board; Modest; Bristol-Myers Squibb. H.A. Schlößer: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Significant; Astra Zeneca.

scholarly journals SFTPA1 is a potential prognostic biomarker correlated with immune cell infiltration and response to immunotherapy in lung adenocarcinoma

2021 ◽  
Author(s):  
Lu Yuan ◽  
Xixi Wu ◽  
Longshan Zhang ◽  
Mi Yang ◽  
Xiaoqing Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Lung Adenocarcinoma ◽  
Expression Profile ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Regulatory Pathways ◽  
Chronic Lung Diseases ◽  
Potential Biomarker

AbstractPulmonary surfactant protein A1 (SFTPA1) is a member of the C-type lectin subfamily that plays a critical role in maintaining lung tissue homeostasis and the innate immune response. SFTPA1 disruption can cause several acute or chronic lung diseases, including lung cancer. However, little research has been performed to associate SFTPA1 with immune cell infiltration and the response to immunotherapy in lung cancer. The findings of our study describe the SFTPA1 expression profile in multiple databases and was validated in BALB/c mice, human tumor tissues, and paired normal tissues using an immunohistochemistry assay. High SFTPA1 mRNA expression was associated with a favorable prognosis through a survival analysis in lung adenocarcinoma (LUAD) samples from TCGA. Further GeneOntology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses showed that SFTPA1 was involved in the toll-like receptor signaling pathway. An immune infiltration analysis clarified that high SFTPA1 expression was associated with an increased number of M1 macrophages, CD8+ T cells, memory activated CD4+ T cells, regulatory T cells, as well as a reduced number of M2 macrophages. Our clinical data suggest that SFTPA1 may serve as a biomarker for predicting a favorable response to immunotherapy for patients with LUAD. Collectively, our study extends the expression profile and potential regulatory pathways of SFTPA1 and may provide a potential biomarker for establishing novel preventive and therapeutic strategies for lung adenocarcinoma.

scholarly journals Enhanced CD4+ and CD8+ T cell infiltrate within convex hull defined pancreatic islet borders as autoimmune diabetes progresses

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alexander J. Dwyer ◽  
Jacob M. Ritz ◽  
Jason S. Mitchell ◽  
Tijana Martinov ◽  
Mohannad Alkhatib ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Convex Hull ◽  
Pancreatic Islets ◽  
Immune Cell ◽  
Nod Mice ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Analytical Strategy ◽  
Islet Mass

AbstractThe notion that T cell insulitis increases as type 1 diabetes (T1D) develops is unsurprising, however, the quantitative analysis of CD4+ and CD8+ T cells within the islet mass is complex and limited with standard approaches. Optical microscopy is an important and widely used method to evaluate immune cell infiltration into pancreatic islets of Langerhans for the study of disease progression or therapeutic efficacy in murine T1D. However, the accuracy of this approach is often limited by subjective and potentially biased qualitative assessment of immune cell subsets. In addition, attempts at quantitative measurements require significant time for manual analysis and often involve sophisticated and expensive imaging software. In this study, we developed and illustrate here a streamlined analytical strategy for the rapid, automated and unbiased investigation of islet area and immune cell infiltration within (insulitis) and around (peri-insulitis) pancreatic islets. To this end, we demonstrate swift and accurate detection of islet borders by modeling cross-sectional islet areas with convex polygons (convex hulls) surrounding islet-associated insulin-producing β cell and glucagon-producing α cell fluorescent signals. To accomplish this, we used a macro produced with the freeware software ImageJ equipped with the Fiji Is Just ImageJ (FIJI) image processing package. Our image analysis procedure allows for direct quantification and statistical determination of islet area and infiltration in a reproducible manner, with location-specific data that more accurately reflect islet areas as insulitis proceeds throughout T1D. Using this approach, we quantified the islet area infiltrated with CD4+ and CD8+ T cells allowing statistical comparison between different age groups of non-obese diabetic (NOD) mice progressing towards T1D. We found significantly more CD4+ and CD8+ T cells infiltrating the convex hull-defined islet mass of 13-week-old non-diabetic and 17-week-old diabetic NOD mice compared to 4-week-old NOD mice. We also determined a significant and measurable loss of islet mass in mice that developed T1D. This approach will be helpful for the location-dependent quantitative calculation of islet mass and cellular infiltration during T1D pathogenesis and can be combined with other markers of inflammation or activation in future studies.

scholarly journals Defining HIV-1 Envelope N-Glycan Microdomains through Site-Specific Heterogeneity Profiles

2018 ◽  
Vol 93 (1) ◽  
Author(s):  
Audra A. Hargett ◽  
Qing Wei ◽  
Barbora Knoppova ◽  
Stacy Hall ◽  
Zhi-Qiang Huang ◽  
...  
Keyword(s):  
Immune System ◽  
Immune Evasion ◽  
Immune Escape ◽  
High Resolution Mass Spectrometry ◽  
National Laboratory ◽  
Site Specific ◽  
Los Alamos National Laboratory ◽  
Glycosylation Sites ◽  
Env Protein ◽  
Hiv 1

ABSTRACT The HIV-1 envelope (Env) glycans shield the surface of Env from the immune system and form integral interactions important for a functional Env. To understand how individual N-glycosylation sites (NGS) coordinate to form a dynamic shield and evade the immune system through mutations, we tracked 20 NGS in Env from HIV-transmitted/founder (T/F) and immune escape variants and their mutants involving the N262 glycan. NGS were profiled in a site-specific manner using a high-resolution mass spectrometry (MS)-based workflow. Using this site-specific quantitative heterogeneity profiling, we empirically characterized the interdependent NGS of a microdomain in the high-mannose patch (HMP). The changes (shifts) in NGS heterogeneity between the T/F and immune escape variants defined a range of NGS that we further probed for exclusive combinations of sequons in the HMP microdomain using the Los Alamos National Laboratory HIV sequence database. The resultant sequon combinations, including the highly conserved NGS N262, N448, and N301, created an immune escape map of the conserved and variable sequons in the HMP microdomain. This report provides details on how some clustered NGS form microdomains that can be identified and tracked across Env variants. These microdomains have a limited number of N-glycan-sequon combinations that may allow the anticipation of immune escape variants. IMPORTANCE The Env protein of HIV is highly glycosylated, and the sites of glycosylation can change as the virus mutates during immune evasion. Due to these changes, the glycan location and heterogeneity of surrounding N-glycosylation sites can be altered, resulting in exposure of different glycan or proteoglycan surfaces while still producing a viable HIV variant. These changes present a need for vaccine developers to identify Env variants with epitopes most likely to induce durable protective responses. Here we describe a means of anticipating HIV-1 immune evasion by dividing Env into N-glycan microdomains that have a limited number of N-glycan sequon combinations.

scholarly journals Development of an Immune-Related Gene Signature for Prognosis in Melanoma

2021 ◽  
Vol 10 ◽  
Author(s):  
Jia-An Zhang ◽  
Xu-Yue Zhou ◽  
Dan Huang ◽  
Chao Luan ◽  
Heng Gu ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Cell ◽  
Treatment Method ◽  
Gene Signature ◽  
Cell Infiltration ◽  
Venn Diagram ◽  
Immune Cell Infiltration ◽  
Tumor Purity ◽  
New Treatment ◽  
Immune Related Genes

Melanoma remains a potentially deadly malignant tumor. The incidence of melanoma continues to rise. Immunotherapy has become a new treatment method and is widely used in a variety of tumors. Original melanoma data were downloaded from TCGA. ssGSEA was performed to classify them. GSVA software and the "hclust" package were used to analyze the data. The ESTIMATE algorithm screened DEGs. The edgeR package and Venn diagram identified valid immune-related genes. Univariate, LASSO and multivariate analyses were used to explore the hub genes. The "rms" package established the nomogram and calibrated the curve. Immune infiltration data were obtained from the TIMER database. Compared with that of samples in the high immune cell infiltration cluster, we found that the tumor purity of samples in the low immune cell infiltration cluster was higher. The immune score, ESTIMATE score and stromal score in the low immune cell infiltration cluster were lower. In the high immune cell infiltration cluster, the immune components were more abundant, while the tumor purity was lower. The expression levels of TIGIT, PDCD1, LAG3, HAVCR2, CTLA4 and the HLA family were also higher in the high immune cell infiltration cluster. Survival analysis showed that patients in the high immune cell infiltration cluster had shorter OS than patients in the low immune cell infiltration cluster. IGHV1-18, CXCL11, LTF, and HLA-DQB1 were identified as immune cell infiltration-related DEGs. The prognosis of melanoma was significantly negatively correlated with the infiltration of CD4+ T cells, CD8+ T cells, dendritic cells, neutrophils and macrophages. In this study, we identified immune-related melanoma core genes and relevant immune cell subtypes, which may be used in targeted therapy and immunotherapy of melanoma.

Soluble IL2R (CD25), IL10 and PDL1 May Control T Cell Activation in Chronic Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4252-4252
Author(s):  
Lisa Christiansson ◽  
Camilla Lindqvist ◽  
Thomas H Tötterman ◽  
Bengt Simonsson ◽  
Ulla Olsson-Strömberg ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Myeloid Leukemia ◽  
Cell Activation ◽  
Immune Escape ◽  
Death Receptor ◽  
T Cell Proliferation ◽  
Programmed Death ◽  
Immune Escape Mechanisms

Abstract Abstract 4252 Cancer patients are known to have an impaired anti-tumor immune response because of various immune escape mechanisms exerted by the tumor cells. These mechanisms involve release of soluble molecules and expression of membrane-bound proteins inhibiting different arms of the anti-tumor immune responses. The immune escape mechanisms seen in cancer patients complicate the use of immunotherapy, such as tumor vaccines and adoptive T cell transfer. The aim of our study was to investigate the presence of IL10, soluble IL2R (sIL2R; CD25) and programmed death receptor ligand 1 (PDL1) in patients with chronic myeloid leukemia (CML) and to study their role as T cell inhibitors. IL10, sIL2R and PDL1 are all known immune inhibitory molecules. IL10 is a secreted molecule that has various suppressive effects on many different immune cells. sIL2R binds IL2 efficiently and may thereby prevent the binding of IL2 to IL2R on T cells, an interaction that is necessary for proliferation and maintenance of tumor-specific T cells. PDL1-expressing tumor cells can bind programmed death receptor 1 (PD1) on T cells. This interaction can induce apoptosis in the T cells. In this study, we used cytometric bead array, ELISA and multicolor flow cytometry to screen CML patients and healthy controls for the presence of IL10, sIL2R and PDL1 in blood. Further, Alamar Blue TM assay and IFNγ detection by flow cytometry were used to investigate T cell proliferation and activation in the presence of the inhibitors. We found that the levels of IL10 and sIL2R were increased in CML patient plasma compared to the levels in healthy control subjects. The level of sIL2R in a subgroup of patients was four-fold higher than the mean level of healthy controls. Patient T cells stimulated with various strong T cell stimuli including CML-specific peptides failed to respond to stimuli as measured by flow cytometric detection of the cytotoxic T cell activation marker IFNγ, indicating that these T cells might be anergic. In vitro studies on T cells from healthy donors showed that both IL10 and sIL2R have the ability to inhibit T cell proliferation. Half of the CML patients had a PDL1 expression on the CD34 cell population raging from 1-36%. PDL1 may, hence, be involved in T cell control in CML. Taken together, our results show that T cells from CML patients fail to respond to stimuli and that these T cells may be controlled by the high levels of IL10, sIL2R and PDL1 seen in the patients. Screening for these inhibitors may aid selection of patients considered for immunotherapy. Disclosures: Simonsson: Novartis: Consultancy, Honoraria, Research Funding, Sponsor; BMS: Consultancy, Honoraria, Research Funding, Sponsor; SCHERING-PLOUGH: Sponsor. Olsson-Strömberg:BMS: Honoraria.

Distinct genomic and immune microenvironment between thymomas and thymic carcinomas.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13529-e13529
Author(s):  
Kaicheng Wang ◽  
Suxia Lin ◽  
Xue Hou ◽  
Yongdong Liu ◽  
Meichen Li ◽  
...  
Keyword(s):  
Immune Cell ◽  
Immune Escape ◽  
Nk Cell ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Immune Microenvironment ◽  
Tissue Samples ◽  
Thymic Epithelial Tumors ◽  
Immune Infiltration ◽  
Thymic Carcinomas

e13529 Background: Thymomas and thymic carcinomas which uniformly known as thymic epithelial tumors (TETs) are rare intrathoracic malignancies and a limited studies have been reported addressing the molecular biology and immune discrepancy. The main purpose of this study was to depict the genomic and transcriptomic landscape of thymomas and thymic carcinomas, as well as elucidate the differentiated immune microenvironment. Methods: Totally 15 thymomas and 7 thymic carcinomas patients were enrolled from January 2014 to July 2018. Treatment-naïve tissue samples were collected, and we also obtained matched peripheral blood mononucleocytes as negative control. DNA and RNA were co-extracted and performed with whole exon and transcriptome sequencing. The immune cell infiltration scores were estimated using ssGSEA algorithm. Results: Exome sequencing revealed that GTF2I mutation occurred in all of type A thymomas but was absent in the aggressive subtypes. The median tumor mutation burden of thymomas was 0.12/Mb, significantly lower than thymic carcinomas (median: 1.02/Mb, p = 0.001). Copy number variation was more common in thymic carcinomas than thymomas (83.3% vs 9.1%, p = 0.005). Top mutational signatures enriched in both thymomas and thymic carcinomas included age and Aristolochic acid exposure, while the APOBEC signature was more common in thymomas than thymic carcinomas (81.8% vs 16.7%, p = 0.03). As a confirmed immune escape event, loss of heterozygosity of human leukocyte antigen was identified in 9.1% of thymomas and 50% of thymic carcinomas. Via unsupervised clustering of immune infiltration, all tissue samples were classified into high- and low-infiltration subgroups. Remarkably, up to 71.4% of samples from thymic carcinomas and only 6.7% of samples from thymomas were defined as low immune cell infiltration. In consideration of specific immune cell types, macrophage ( p = 0.01) and neutrophil ( p = 0.02) were enriched in thymic carcinomas while CD56+ NK cell ( p = 0.005) was enriched in thymomas, indicating the evidential discrepancy about immune cell infiltration between two subtypes of TETs. Conclusions: This study elucidated the molecular and immune microenvironment discrepancy between two subtypes of TETs. From molecular perspective, thymomas and thymic carcinomas are entirely different diseases with different etiology and characterized by distinct immune infiltration, and thus should be managed with disparate therapeutic strategies. Findings in this study may also be useful in future targets development and exploration of immunotherapies in TETs.

scholarly journals Evolution of immune escape mechanisms in the progression from preinvasive to invasive human lung adenocarcinoma

2020 ◽  
Author(s):  
Nasser K. Altorki ◽  
Alain C. Borczuk ◽  
Vivek Mittal ◽  
Olivier Elemento ◽  
Timothy E. McGraw
Keyword(s):  
T Cells ◽  
Minimally Invasive ◽  
Lung Adenocarcinoma ◽  
Disease Progression ◽  
Immune Escape ◽  
Cytotoxic T Cells ◽  
Treg Cells ◽  
Normal Lung ◽  
Ct Density ◽  
Immune Escape Mechanisms

SummaryThe tumor microenvironment (TME) of lung adenocarcinoma (LUAD) precursor lesions has not been described. We interrogated by multiplex immunofluorescence the TME of preinvasive and invasive Stage 1A LUADs selected by computer tomography (CT) scan-density. Pure non-solid (p-NS) CT density nodules are preinvasive/minimally invasive, whereas solid CT density nodules are frankly invasive cancers. Our data reveal an intensely immune-suppressive immune TME in p-NS tumors characterized by an increase in Treg cells and a decrease in cytotoxic T cells relative to normal lung. The TME of the solid tumor group, more advanced lesions than the p-NS yet still early in disease development, were increasingly more immune-suppressive. Provocatively, there was a further increase in both Treg cells and cytotoxic T cells, establishing a nascent albeit ineffective anti-tumor immune response in transition from preinvasive p-NS to invasive solid tumors. Regulatory T cells play a dominant role throughout progression, while additional immune evasive mechanisms are employed at different stages of disease progression, including T cell exclusion from cancer cell nests early and activation of immune checkpoints later. Our study establishes that different immune-targeted strategies are required to intercept disease progression at these two distinct early points of lung cancer development.Statement of SignificanceUsing multiplexed IF, we compared the cellular composition and activation state of the tumor immune microenvironment between pre/minimally invasive and frankly invasive adenocarcinoma. We found a progressive increase in immunosuppressive mechanisms in association with disease progression suggesting that Interception strategies should be specifically tailored based on underlying immune escape mechanisms

scholarly journals B2M Gene Expression Reflects an Immunologically Active Tumor Microenvironment in DLBCL

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2778-2778
Author(s):  
Clare Gould ◽  
Colm Keane ◽  
Valentine Murigneux ◽  
Harald Oey ◽  
Jonathan Ellis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Microenvironment ◽  
Antigen Presentation ◽  
Board Of Directors ◽  
Research Funding ◽  
Immune Cell ◽  
Immune Cell Infiltration ◽  
Protein Loss ◽  
Advisory Committees ◽  
Immune Effector

Introduction Interactions between tumor cells and the immune system play a critical role in regulating tumor development. Immune-based therapies have shown variable responses in diffuse large B-cell lymphoma (DLBCL) which suggests that the immune cell composition of the tumor microenvironment (TME) influences response to these agents. However, the key determinants of the immune TME are poorly understood. We have recently shown that indolent lymphomas can be stratified as immunologically 'hot' or 'cold' (Tobin et al J. Clin Oncol, in press) and sought to test for this in DLBCL. Also, given that beta-2-microglobulin (B2M) has a key role in antigen presentation and its loss is a frequent immune evasion mechanism in DLBCL, we determined the effect of B2M expression on the nature and magnitude of immune infiltration in the tumor microenvironment of DLBCL. Methods Ninety-seven de novo systemic DLBCL FFPE biopsies underwent targeted exon re-sequencing of B2M (Illumina) in addition to quantitative gene expression of Β2M, immune effector (CD4, CD8, CD56, CD137), immunosuppressive macrophage markers (CD68, CD163) and immune checkpoints (TIM3, LAG3, PD1 and PDL1) (Nanostring Technologies). B2M promoter methylation by mass array, immunohistochemistry for the above markers and high throughput T-cell receptor β sequencing (Adaptive Biotechnologies) were performed on a subset of cases. Genomic findings were validated in a whole exome and transcriptome cohort of approximately 1000 DLBCL samples (Reddy et al Cell 2017). Results Β2MMut were detected in 14/97 (14.4%) samples and had lower Β2M gene expression compared to Β2MWT (p = 0.0094) and all of these showed B2M protein loss. However, 29/40 (72%) of B2MWT samples tested also had B2M protein loss. There was no differential methylation of B2M promoter regions observed compared to lymph node controls. Results indicate that mechanisms other than mutation and methylation status contribute to loss of B2M surface expression and that a more comprehensive assessment of B2M expression within tumor tissues is achieved by B2M digital gene quantification. Consistent with this, there were no significant differences in expression of intra-tumoral immune markers between B2MMut and B2MWT tissues, whereas gene expression of B2M was significantly associated and positively correlated with the gene expression of CD4, CD8, CD56, CD137, CD68, CD163, PD1, PDL1, LAG3 and TIM3 (all p <0.01) and with the protein expression of CD8, CD56, CD137, PDL1 and LAG3 (all p <0.01), irrespective of their classification as an immune-effector, immune-checkpoint or macrophage markers. These observations are consistent with a co-ordinately regulated immune response, indicating an adaptive immune-checkpoint response to regulate immune-effector activation. In keeping with this, the housekeeper genes did not correlate with immune gene expression indicating that high or low co-ordinate expression of immune genes was not reflecting tissue RNA quality or quantity (Fig 1). Next, we tested the discovery cohort for relationships with the TCR repertoire. High B2M gene expression was significantly associated with reduced TCR diversity (p = 0.0101) compared to low B2M gene expression, suggesting that clonal T cell expansions are more likely with intact antigen presentation. The validation cohort also demonstrated that B2M gene expression correlated with immune cell infiltration and additionally showed that B2M positively correlated with the gene expression of HLA Class I//II molecules and a range of regulatory, transport and assembly molecules involved in the antigen presentation machinery pathway. However, no differential survival benefit was observed in patients with high versus low B2M. Conclusions In summary, digital gene expression is a robust measure of B2M quantification in the TME. Our data show that high B2M gene expression reflects an immunologically active or 'hot' tumor microenvironment in DLBCL characterised by higher levels of immune cell infiltration. These findings indicate that B2M gene expression level could be used as a biomarker of an active intra-tumoral immune response in DLBCL. Further studies are required to determine if B2M gene expression may have a role in stratifying the selection of patients in whom immune-based therapies are more likely to be effective. Disclosures Gould: NovoNordisk: Other: Travel funding - domestic flights to attend education, May 2018. Keane:MSD: Consultancy; BMS: Research Funding; Celgene: Consultancy; Gilead: Consultancy; Roche: Consultancy, Other: Travel Grant. Hertzberg:Takeda: Consultancy, Honoraria; MSD: Consultancy; Roche: Consultancy, Honoraria. Gandhi:Gilead: Honoraria, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Other: Travel Support; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria.

scholarly journals Comprehensive Analysis of YTH Domain Family in Lung Adenocarcinoma: Expression Profile, Association with Prognostic Value, and Immune Infiltration

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Kuan Hu ◽  
Lei Yao ◽  
Yuanliang Yan ◽  
Lei Zhou ◽  
Juanni Li
Keyword(s):  
T Cells ◽  
Lung Adenocarcinoma ◽  
Prognostic Value ◽  
Immune Cell ◽  
Expression Profiles ◽  
Family Members ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Domain Family ◽  
Yth Domain

Background. All YTH domain family members are m6A reader proteins accounting for the methylation modulation involved in the process of tumorgenesis and tumor progression. However, the expression profiles and roles of the YTH domain family in lung adenocarcinoma (LUAD) remain to be further illustrated. Methods. GEPIA2 and TNMplot databases were used to generate the expression profiles of the YTH family. Kaplan-Meier plotter database was employed to analysis the prognostic value of the YTH family. Coexpression profiles and genetic alterations analysis of the YTH family were undertaken using the cBioPortal database. YTH family protein-associated protein-protein interaction (PPI) network was identified by using STRING. Functional enrichment analysis was performed with the help of the WebGestalt database. The correlation analysis between the YTH family and immune cell infiltration in LUAD was administrated by using the TIMER2.0 database. Results. mRNA expression of YTHDC1 and YTHDC2 was significantly lower in LUAD, whereas YTHDF1, YTHDF2, and YTHDF3 with apparently higher expression. YTHDF2 expression was observed to be the highest in the nonsmoker subgroup, and its expression gradually decreased with the increased severity of smoking habit. LUAD patients with low expression of YTHDC2, YTHDF1, and YTHDF2 were correlated with a better overall survival (OS) time. The YTHDF1 genetic alteration rate was 26%, which was the highest in the YTH family. The major cancer-associated functions of YTH family pointed in the direction of immunomodulation, especially antigen processing and presentation. Most of the YTH family members were significantly correlated with the infiltration of CD4+ T cells, CD8+ T cells, macrophages, and neutrophils, indicating the deep involvement of the YTH domain family in the immune cell infiltration in LUAD. Conclusion. The molecular and expression profiles of the YTH family were dysregulated in LUAD. YTH family members (especially YTHDC2) were promising biomarkers and potential therapeutic targets that may bring benefit for the patients with LUAD.

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