Computational recognition of lncRNA signature of tumor-infiltrating B lymphocytes with potential implications in prognosis and immunotherapy of bladder cancer

2020 ◽  
Author(s):  
Meng Zhou ◽  
Zicheng Zhang ◽  
Siqi Bao ◽  
Ping Hou ◽  
Congcong Yan ◽  
...  
Keyword(s):  
B Lymphocytes ◽  
Noncoding Rna ◽  
Immune Cell ◽  
Functional Characterization ◽  
Predictive Biomarkers ◽  
Computational Framework ◽  
Gene Markers ◽  
Programmed Death ◽  
Clinical Covariates ◽  
Programmed Death 1

Abstract Long noncoding RNAs (lncRNAs) have been associated with cancer immunity regulation and the tumor microenvironment (TME). However, functions of lncRNAs of tumor-infiltrating B lymphocytes (TIL-Bs) and their clinical significance have not yet been fully elucidated. In the present study, a machine learning-based computational framework is presented for the identification of lncRNA signature of TIL-Bs (named ‘TILBlncSig’) through integrative analysis of immune, lncRNA and clinical profiles. The TILBlncSig comprising eight lncRNAs (TNRC6C-AS1, WASIR2, GUSBP11, OGFRP1, AC090515.2, PART1, MAFG-DT and LINC01184) was identified from the list of 141 B-cell-specific lncRNAs. The TILBlncSig was capable of distinguishing worse compared with improved survival outcomes across different independent patient datasets and was also independent of other clinical covariates. Functional characterization of TILBlncSig revealed it to be an indicator of infiltration of mononuclear immune cells (i.e. natural killer cells, B-cells and mast cells), and it was associated with hallmarks of cancer, as well as immunosuppressive phenotype. Furthermore, the TILBlncSig revealed predictive value for the survival outcome and immunotherapy response of patients with anti-programmed death-1 (PD-1) therapy and added significant predictive power to current immune checkpoint gene markers. The present study has highlighted the value of the TILBlncSig as an indicator of immune cell infiltration in the TME from a noncoding RNA perspective and strengthened the potential application of lncRNAs as predictive biomarkers of immunotherapy response, which warrants further investigation.

scholarly journals Immunotherapy Predictive Molecular Markers in Advanced Gastroesophageal Cancer: MSI and Beyond

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1715
Author(s):  
Robin Park ◽  
Laercio Lopes ◽  
Anwaar Saeed
Keyword(s):  
Treatment Options ◽  
Unmet Need ◽  
Predictive Biomarkers ◽  
Phase Iii ◽  
Gastroesophageal Cancer ◽  
Programmed Death ◽  
Phase Iii Trials ◽  
Tumor Mutational Burden ◽  
Large Phase ◽  
Programmed Death 1

Advanced gastroesophageal cancer (GEC) has a poor prognosis and limited treatment options. Immunotherapy including the anti-programmed death-1 (PD-1) antibodies pembrolizumab and nivolumab have been approved for use in various treatment settings in GEC. Additionally, frontline chemoimmunotherapy regimens have recently demonstrated promising efficacy in large phase III trials and have the potential to be added to the therapeutic armamentarium in the near future. There are currently several immunotherapy biomarkers that are validated for use in the clinical setting for GEC including programmed death ligand-1 (PD-L1) expression as well as the tumor agnostic biomarkers such as mismatch repair or microsatellite instability (MMR/MSI) and tumor mutational burden (TMB). However, apart from MMR/MSI, these biomarkers are imperfect because none are highly sensitive nor specific. Therefore, there is an unmet need for immunotherapy biomarker development. To this end, several biomarkers are currently being evaluated in ongoing trials with some showing promising predictive potential. Here, we summarize the landscape of immunotherapy predictive biomarkers that are currently being evaluated in GEC.

scholarly journals Genomic profiling of advanced cervical cancer to predict response to programmed death-1 inhibitor combination therapy: a secondary analysis of the CLAP trial

2021 ◽  
Vol 9 (5) ◽  
pp. e002223
Author(s):  
Xin Huang ◽  
Minjun He ◽  
Hongyu Peng ◽  
Chongjie Tong ◽  
Zhimin Liu ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Combination Therapy ◽  
Secondary Analysis ◽  
Predictive Biomarkers ◽  
Genetic Alterations ◽  
Akt Pathway ◽  
Advanced Cervical Cancer ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Inhibitor Combination

BackgroundThe Camrelizumab Plus Apatinib in Patients with Advanced Cervical Cancer trial was a single-arm, phase II study that showed promising activity of the programmed death-1 (PD-1) inhibitor camrelizumab plus the vascular endothelial growth factor receptor-2 inhibitor apatinib in patients with advanced cervical cancer. However, the predictive biomarkers for treatment outcomes are unknown. In this study, we aimed to identify potential predictors of treatment response in PD-1 inhibitor combination therapy.MethodsGenomic profiling was performed on patients with available biopsy or surgical samples by targeted next-generation sequencing of 425 cancer-related genes in this preplanned, secondary analysis. Somatic alterations, including all non-synonymous mutations, and tumor mutational burden (TMB) were assessed for their predictive values in objective response rate, progression-free survival (PFS), and overall survival (OS).ResultsA subset of 32 patients was included in this analysis. Top altered genes included PIK3CA (43.8%), STK11 (25%), FBXW7 (15.6%), and PTEN (15.6%). The PI3K/AKT pathway was among the most frequently dysregulated pathways, and its genetic alterations were identified in 68.8% of patients. PIK3CA (PFS HR 0.33, p=0.05; OS HR 0.23, p=0.04) and PTEN (PFS HR 3.71e-09, p=0.05; OS HR 3.64e-09, p=0.08) alterations were associated with improved outcomes. PI3K/AKT pathway genetic alterations showed improved predictive power compared with either PIK3CA or PTEN alterations alone (PFS HR 0.33, p=0.03; OS HR 0.25, p=0.02), while ERBB3 mutations (PFS HR 34.9, p<0.001; OS HR 19.8, p<0.001) correlated with poor survival. TMB-high (≥5 mut/Mb) was associated with prolonged PFS (HR 0.26, p<0.01) and OS (HR 0.31, p=0.05). Multivariate analysis showed ERBB3 mutations (PFS p=0.01, OS p<0.001), PD-L1 positive (PFS p=0.01, OS p=0.05), and high TMB (PFS p=0.01, OS p=0.05) remained significantly associated with survival.ConclusionsWe uncovered that genetic alterations in PIK3CA, PTEN, ERBB3, and PI3K/AKT pathway, as well as TMB, could be novel predictive biomarkers in patients with cervical cancer treated with PD-1 inhibitor combination therapy.Trial registration numberNCT03816553.

scholarly journals Immune checkpoint inhibitors in ovarian cancer: where do we stand?

2021 ◽  
Vol 13 ◽  
pp. 175883592110398
Author(s):  
Alexandra Leary ◽  
David Tan ◽  
Jonathan Ledermann
Keyword(s):  
Ovarian Cancer ◽  
Retrospective Studies ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Parp Inhibitors ◽  
Early Results ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Immune Oncology

Numerous retrospective studies have demonstrated that the density of intra-tumoral immune cell infiltration is prognostic in epithelial ovarian cancer (OC). These observations together with reports of programmed death ligand-1 (PD-L1) expression in advanced OC provided the rationale for investigating the benefit of programmed death-1 (PD1) or PD-L1 inhibition in OC. Unfortunately clinical trials to date evaluating PD1/PD-L1 inhibition in patients with relapsed OC have been disappointing. In this review we will discuss early results from single agent PD1/PD-L1 inhibitors and the strategies to enhance benefit from immune-oncology agents in OC, including proposing anti-PD-L1 in combination with other agents (cytotoxics, anti-angiogenics, poly(ADP-ribose) polymerase. (PARP) inhibitors, targeted therapies or other immunotherapies), as well as evaluating these agents earlier in the disease course, or in biomarker selected patients.

scholarly journals Immune-checkpoint engagement as predictive biomarkers in clear cell renal cell carcinoma and melanoma

2020 ◽  
Author(s):  
Lissete Sánchez-Magraner ◽  
James Miles ◽  
Claire Baker ◽  
Christopher J Applebee ◽  
Dae-Jin Lee ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Expression Patterns ◽  
Predictive Biomarkers ◽  
Immune Checkpoints ◽  
Ligand Interaction ◽  
Receptor Ligand ◽  
Programmed Death ◽  
Cell Cell

ABSTRACTMany cancers are termed immuno-evasive due to expression of immuno-modulatory ligands. Programmed death ligand-1 (PD-L1) and cluster of differentiation 80/86 (CD80/86) interact with their receptors, programmed death receptor-1 (PD-1) and cytotoxic T-lymphocyte associated protein-4 (CTLA-4), on tumour infiltrating leukocytes, thus eliciting immunosuppression. Immunotherapies aimed at blocking these interactions are revolutionising cancer treatments, albeit in an inadequately described patient subset.Our prognostic assay, utilising amplified two-site time-resolved Förster resonance energy transfer (iFRET), quantifies PD-1/ PD-L1 and CTLA-4/ CD80 cell-cell interactions in single cell assays and tumour biopsies. iFRET efficiencies demonstrate, in cell-cell engagement models, that receptor-ligand interactions are significantly lower with anti-PD-1 or anti-CTLA-4 blocking antibodies. In patient samples, iFRET detects immune-cell/tumour-cell interaction variance in different cancers. These results revealed inter-cancer, inter-patient and intra-tumoural heterogeneity of engaged immune-checkpoints, contradicting their ligand expression patterns. Exploiting spatio-temporal interactions of immune-checkpoint proteins defined biomarker functionality for determining whether checkpoint inhibitors are appropriate treatments.Statement of SignificanceQuantitative photophysics exploitation in determining immune-checkpoint engagement, as predictive biomarkers in cancers led to revealing inter-cancer, inter-patient and intra-tumoural heterogeneity of the engaged immune-checkpoints. This receptor-ligand interaction did not reflect simple expression patterns of these immuno-modulatory proteins. Our findings may affect immunotherapies aimed at blocking these intercellular interactions in patients.

scholarly journals PD-L1 in Cytological Samples: A Review and a Practical Approach

2021 ◽  
Vol 8 ◽  
Author(s):  
Eva Tejerina ◽  
Laura García Tobar ◽  
José I. Echeveste ◽  
Carlos E. de Andrea ◽  
Elena Vigliar ◽  
...  
Keyword(s):  
Predictive Biomarkers ◽  
Cost Effective ◽  
Standard Of Care ◽  
Observer Agreement ◽  
Cancer Treatments ◽  
Formalin Fixed Paraffin ◽  
Programmed Death ◽  
Wide Range ◽  
Formalin Fixed Paraffin Embedded ◽  
Programmed Death 1

With a growing number of predictive biomarkers needed to manage patients with non-small cell lung cancer (NSCLC), there has been a paradigm shift in care and handling of diagnostic samples. Among the various testing methods, immunohistochemistry (IHC) is the most cost- effective and widely available. Furthermore, over the past decade immunotherapy has emerged as one of the most promising cancer treatments. In this scenario IHC is the most used testing method available for PDL-1/PD1 immunotherapy. Several monoclonal antibodies targeting programmed death 1 (PD-1)/programmed death ligand-1 (PD-L1) pathways have been integrated into standard-of-care treatments of a wide range of cancer types, once provided evidence of PD-L1 expression in tumor cells by immunohistochemistry (IHC). Since currently available PD-L1 assays have been developed on formalin-fixed paraffin embedded (FFPE) histological specimens, a growing body of research is being dedicated to confirm the feasibility of applying PDL-1 assays also to cytological samples. Albeit promising results have been reported, several important issues still need to be addressed. Among these are the type of cytological samples, pre-analytical issues, cyto-histological correlation, and inter-observer agreement. This review briefly summarizes the knowledge of the role of cytopathology in the analysis of PD-L1 by immunocytochemistry (ICC) and future directions of cytopathology in the immunotherapy setting.

scholarly journals Murine isolated lymphoid follicles contain follicular B lymphocytes with a mucosal phenotype

2006 ◽  
Vol 291 (4) ◽  
pp. G595-G604 ◽  
Author(s):  
Caihong Wang ◽  
Keely G. McDonald ◽  
Jacquelyn S. McDonough ◽  
Rodney D. Newberry
Keyword(s):  
Immune Responses ◽  
B Lymphocytes ◽  
Plasma Cells ◽  
Interferon Γ ◽  
Lymphoid Follicles ◽  
Functional Aspects ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Lymphoid Structures ◽  
Immunoglobulin Repertoire

Isolated lymphoid follicles (ILFs) are organized intestinal lymphoid structures whose formation can be induced by luminal stimuli. ILFs have been demonstrated to act as inductive sites for the generation of immune responses directed toward luminal stimuli; however, the phenotype of the immune response initiated within ILFs has largely been uninvestigated. To gain a better understanding of the immune responses initiated within ILFs, we examined phenotypic and functional aspects of the largest cellular component of the murine ILF lymphocyte population, B lymphocytes. We observed that murine ILF B lymphocytes are composed of a relatively homogenous population of follicular B-2 B lymphocytes. Consistent with their proximity to multiple stimuli, ILF B lymphocytes displayed a more activated phenotype compared with their counterparts in the spleen and Peyer's patch (PP). ILF B lymphocytes also expressed higher levels of immunomodulatory B7 and CD28 family members B7X and programmed death-1 compared with their counterparts in the spleen and PP. ILF B lymphocytes preferentially differentiate into IgA-producing plasma cells and produce more IL-4 and IL-10 and less interferon-γ compared with their counterparts in the spleen. Immunoglobulin repertoire analysis from individual ILFs demonstrated that ILFs contain a polyclonal population of B lymphocytes. These findings indicate that murine ILFs contain a polyclonal population of follicular B-2 B lymphocytes with a phenotype similar to PP B lymphocytes and that, in unchallenged animals, ILFs promote immune responses with a homeostatic phenotype.

scholarly journals Combined PD-1/PD-L1 and tumor-infiltrating immune cells redefined a unique molecular subtype of high-grade serous ovarian carcinoma

BMC Genomics ◽  
2022 ◽  
Vol 23 (1) ◽  
Author(s):  
Ping Liu ◽  
Ruoxu Chen ◽  
Xudong Zhang ◽  
Ruiting Fu ◽  
Lin Tao ◽  
...  
Keyword(s):  
Ovarian Carcinoma ◽  
Immune Cell ◽  
Molecular Subtype ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
High Grade ◽  
Serous Ovarian Carcinoma ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Antigen Presenting

Abstract Background High-grade serous ovarian carcinoma is highly heterogeneous, and although many studies have been conducted to identify high-grade serous ovarian carcinoma molecular subtypes that are sensitive to immunotherapy, no precise molecular subtype has been proposed to date. Immune cell infiltration and immune checkpoints are highly correlated with immunotherapy. Here, we investigated immune cell infiltration and immune checkpoint values for prognosis and precise immunotherapy for high-grade serous ovarian carcinoma based on molecular subtype classification. Results “High antigen-presenting cells infiltration molecular subtype of high-grade serous ovarian carcinoma” was identified in immune cell infiltration profiles. Each of the three immune cell infiltration clusters (A, B, and C) demonstrated distinct immune cell characterization, with immune cell infiltration cluster C exhibiting high antigen-presenting cell infiltration, improved prognosis, and higher sensitivity to immunotherapy. Programmed death-1/programmed death ligand 1 has a prognostic and predictive role that can help classify molecular subtypes. Conclusions Our findings redefined a unique molecular subtype of high-grade serous ovarian carcinoma, suggesting that high-grade serous ovarian carcinoma patients with higher antigen-presenting cell infiltration and programmed death-1/programmed death ligand 1 expression can benefit from precise immunotherapy.

scholarly journals AutoEncoder-Based Computational Framework for Tumor Microenvironment Decomposition and Biomarker Identification in Metastatic Melanoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Yanding Zhao ◽  
Yadong Dong ◽  
Yongqi Sun ◽  
Chao Cheng
Keyword(s):  
Immune Cell ◽  
Tumor Vaccine ◽  
Predictive Biomarkers ◽  
The Cancer Genome Atlas ◽  
Computational Framework ◽  
Aggressive Cancer ◽  
Cancer Genome Atlas ◽  
Cancer Types ◽  
Patient Prognosis ◽  
Microarray Datasets

Melanoma is one of the most aggressive cancer types whose prognosis is determined by both the tumor cell-intrinsic and -extrinsic features as well as their interactions. In this study, we performed systematic and unbiased analysis using The Cancer Genome Atlas (TCGA) melanoma RNA-seq data and identified two gene signatures that captured the intrinsic and extrinsic features, respectively. Specifically, we selected genes that best reflected the expression signals from tumor cells and immune infiltrate cells. Then, we applied an AutoEncoder-based method to decompose the expression of these genes into a small number of representative nodes. Many of these nodes were found to be significantly associated with patient prognosis. From them, we selected two most prognostic nodes and defined a tumor-intrinsic (TI) signature and a tumor-extrinsic (TE) signature. Pathway analysis confirmed that the TE signature recapitulated cytotoxic immune cell related pathways while the TI signature reflected MYC pathway activity. We leveraged these two signatures to investigate six independent melanoma microarray datasets and found that they were able to predict the prognosis of patients under standard care. Furthermore, we showed that the TE signature was also positively associated with patients’ response to immunotherapies, including tumor vaccine therapy and checkpoint blockade immunotherapy. This study developed a novel computational framework to capture the tumor-intrinsic and -extrinsic features and identified robust prognostic and predictive biomarkers in melanoma.

scholarly journals The Mechanisms Leading to Distinct Responses to PD-1/PD-L1 Blockades in Colorectal Cancers With Different MSI Statuses

2021 ◽  
Vol 11 ◽  
Author(s):  
Guanglin Cui
Keyword(s):  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Immune Cell ◽  
Basic Research ◽  
Final Analysis ◽  
Therapeutic Outcomes ◽  
Mutation Burden ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Cell Densities

Current clinical studies showed distinct therapeutic outcomes, in which CRC patients with mismatch repair-deficient (dMMR)/microsatellite instability high (MSI-H) seem to be relatively more “sensitive” in response to anti-programmed death-1 receptor (PD-1)/programmed death-1 receptor ligand 1 (PD-L1) therapy than those with mismatch repair-proficient (pMMR)/microsatellite instability-low (MSI-L). The mechanisms by which the same PD-1/PD-L1 blockades lead to two distinct therapeutic responses in CRC patients with different MSI statuses remain poorly understood and become a topic of great interest in both basic research and clinical practice. In this review of the potential mechanisms for the distinct response to PD-1/PD-L1 blockades between dMMR/MSI-H CRCs and pMMR/MSI-L CRCs, relevant references were electronically searched and collected from databases PubMed, MEDLINE, and Google scholar. Sixty-eight articles with full text and 10 articles by reference-cross search were included for final analysis after eligibility selection according to the guidelines of PRISMA. Analysis revealed that multiple factors e.g. tumor mutation burden, immune cell densities and types in the tumor microenvironment, expression levels of PD-1/PD-L1 and cytokines are potential determinants of such distinct response to PD-1/PD-L1 blockades in CRC patients with different MSI statuses which might help clinicians to select candidates for anti-PD-1/PD-L1 therapy and improve therapeutic response in patients with CRC.

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