scholarly journals Comparative Multiomic Analysis Reveals Low T Cell Infiltration as the Primary Feature of Tobacco Use in HPV(+) Oropharyngeal Cancer

2021 ◽  
Author(s):  
Benjamin M Wahle ◽  
Paul Zolkind ◽  
Ricardo Ramirez ◽  
Zachary L Skidmore ◽  
Angela Mazul ◽  
...  
Keyword(s):  
T Cell ◽  
Tobacco Use ◽  
Disease Free Survival ◽  
Oncologic Outcomes ◽  
Cell Infiltration ◽  
Tobacco Exposure ◽  
Primary Tumors ◽  
T Cell Infiltration ◽  
Mutational Burden ◽  
Whole Exome

Purpose: Tobacco use is an independent adverse prognostic feature in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). Despite this, the biologic features associated with tobacco use have not been systematically investigated in this population. We sought to characterize the genomic and immunologic features of HPV(+) OPSCC associated with tobacco use and adverse oncologic outcomes. Experimental Design: Whole exome sequencing of 47 primary HPV(+) OPSCC tumors was performed to investigate mutational differences associated with tobacco exposure. To characterize the tumor immune microenvironment (TIME), targeted mRNA hybridization was performed and immunohistochemical (IHC) staining was used to validate these findings. Results: Low expression of transcripts in a T cell-inflamed gene expression profile (TGEP) was associated with tobacco use at the time of diagnosis and lower overall and disease-free survival. Tobacco use was associated with an increased proportion of T>C substitutions and a lower proportion of mutational signatures typically observed in HPV(+) OPSCC tumors, but was not associated with increases in mutational burden or the rate of recurrent oncogenic mutations. Conclusions: In HPV(+) OPSCC, low T cell infiltration of primary tumors is associated with current tobacco use and worse oncologic outcomes. Rather than an increased mutational burden, tobacco's primary and clinically relevant association is immunosuppression of the primary TIME. An objective clinical assay like the TGEP, which quantifies immune infiltration of the primary TIME, may have value for HPV(+) OPSCC risk stratification in future clinical trials.

scholarly journals Predicted CD4+ T cell infiltration levels could indicate better overall survival in sarcoma patients

2021 ◽  
Vol 49 (1) ◽  
pp. 030006052098153
Author(s):  
Qing Bi ◽  
Yang Liu ◽  
Tao Yuan ◽  
Huizhen Wang ◽  
Bin Li ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Survival Data ◽  
Tumor Infiltrating Lymphocytes ◽  
The Cancer Genome Atlas ◽  
Cell Infiltration ◽  
T Cell Infiltration ◽  
Whole Exome ◽  
Cancer Genome Atlas ◽  
Infiltrating Lymphocytes

Objective The role of tumor-infiltrating lymphocytes (TILs) has not yet been characterized in sarcomas. The aim of this bioinformatics study was to explore the effect of TILs on sarcoma survival and genome alterations. Methods Whole-exome sequencing, transcriptome sequencing, and survival data of sarcoma were obtained from The Cancer Genome Atlas. Immune infiltration scores were calculated using the Tumor Immune Estimation Resource. Potential associations between abundance of infiltrating TILs and survival or genome alterations were examined. Results Levels of CD4+ T cell infiltration were associated with overall survival of patients with pan-sarcomas, and higher CD4+ T cell infiltration levels were associated with better survival. Somatic copy number alterations, rather than mutations, were found to correlate with CD4+ T cell infiltration levels. Conclusions This data mining study indicated that CD4+ T cell infiltration levels predicted from RNA sequencing could predict sarcoma prognosis, and higher levels of CD4+ T cells infiltration indicated a better chance of survival.

Mutational burden and activated T cell infiltration in lung squamous cell carcinomas with DNA repair mutations.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. 3042-3042
Author(s):  
Young Kwang Chae ◽  
Jonathan Forrest Anker ◽  
Nisha Anjali Mohindra ◽  
Jason B. Kaplan ◽  
Sunandana Chandra ◽  
...  
Keyword(s):  
Dna Repair ◽  
T Cell ◽  
Squamous Cell ◽  
Squamous Cell Carcinomas ◽  
Cell Infiltration ◽  
T Cell Infiltration ◽  
Mutational Burden ◽  
Activated T Cell

scholarly journals Characterization of evolution trajectory and immune profiling of brain metastasis in lung adenocarcinoma

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Tao Jiang ◽  
Yan Yan ◽  
Kun Zhou ◽  
Chunxia Su ◽  
Shengxiang Ren ◽  
...  
Keyword(s):  
Phylogenetic Analysis ◽  
T Cell ◽  
Brain Metastasis ◽  
Lung Adenocarcinoma ◽  
Early Stage ◽  
Cell Infiltration ◽  
Evolutionary Trajectory ◽  
Primary Tumors ◽  
T Cell Infiltration ◽  
Immune Profiling

AbstractCharacterizing the evolutionary trajectory and immune profiling of brain metastasis (BM) may provide insights in the development of novel therapeutic strategies. Here, we performed whole-exome sequencing and multiplex immunofluorescence (MIF) of 40 samples from 12 lung adenocarcinoma (LUAD) patients with BM and compared to their paired primary tumors. We observed significantly higher intertumor heterogeneity between paired primary tumors and BMs, with only a median of 8.3% of genetic mutations identified as shared. Phylogenetic analysis revealed that BM-competent clones genetically diverged from their primary tumors at relatively early stage, suggesting that the parallel progression model is dominant. In cases with synchronous lymph node metastasis (LNM), phylogenetic analysis suggested that BM is a later event than LNM. MIF analysis found that BMs exhibited significantly lower CD8+ T cell infiltration (P = 0.048), and elevated CD4+Foxp3+ T cell infiltration (P = 0.036) and PD-1 expression (P = 0.047) in comparison to the matched primary tumors, indicating an immunosuppressive microenvironment in BMs. The current study revealed the discrepancy of mutational landscape as well as tumor immune microenvironment between BM and its primary tumor – such findings shall help us better understand the unique biological features of BM and develop innovative strategies accordingly for our patients with LUAD.

scholarly journals The frequency and inter-relationship of PD-L1 expression and tumour mutational burden across multiple types of advanced solid tumours in China

2020 ◽  
Author(s):  
Yanhui Chen ◽  
Yating Wang ◽  
Hongli Luo ◽  
Xue Meng ◽  
Wei Zhu ◽  
...  
Keyword(s):  
T Cell ◽  
Solid Tumours ◽  
Chinese Patients ◽  
Cell Infiltration ◽  
Cancer Subtypes ◽  
T Cell Infiltration ◽  
Mutational Burden ◽  
Multiple Biomarkers ◽  
Effect Of Pd ◽  
Relationship Of

Abstract Background: PD-L1 expression and tumour mutational burden (TMB) have been demonstrated to be associated with the responses of multiple tumours to ICI therapy. Their prevalence and correlations in various types of advanced solid tumours from Chinese patients warrant further study. Methods: PD-L1 expression, TMB, PD-1+ Tils infiltration and the relationships among them were assessed in 6,668 advanced solid tumour specimens across 25 tumour types. The relationships among PD-L1 expression, TMB, PD-1+ Tils and CD8+ T cell infiltration and the therapeutic effect of PD-1 inhibitors were analysed in NSCLC samples.Results: PD-L1 expression and TMB varied widely among tumour types. PD-L1 expression and TMB was not significantly correlated within most cancer subtypes, and they showed only a small association across all specimens (Spearman R = 0.059). PD-1+ Tils infiltration was correlated with PD-L1 expression across all samples (Spearman R = 0.3056). However, PD-1+ Tils infiltration and TMB were not correlated. In NSCLC samples, CD8+ T cell infiltration was correlated with PD-1+ Tils infiltration and PD-L1 expression but not with TMB (Spearman R = 0.4117, 0.2045, 0.0007). Patients in the CR/PR group (anti-PD-1 therapy) had higher levels of PD-L1 expression, TMB, PD-1+ Tils and CD8+ T cell infiltration, and more patients in this group exhibited elevated levels of multiple biomarkers. Conclusions: Our results showed the PD-L1 expression and TMB in various types of advanced solid tumours in Chinese patients and their relationship with PD-1+ Tils and CD8+ T cell infiltration, which may inform ICI treatment.

The association of CD8+ T-cell infiltration and PD-L1 expression with prognosis of Chinese pulmonary large cell neuroendocrine carcinoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21003-e21003
Author(s):  
Ye Li ◽  
Xinying Shi ◽  
Jinliang Wang ◽  
Beibei Mao ◽  
Jie Li ◽  
...  
Keyword(s):  
T Cell ◽  
Neuroendocrine Carcinoma ◽  
Univariate Analysis ◽  
Disease Free Survival ◽  
Large Cell ◽  
Cd8 T Cell ◽  
Large Cell Neuroendocrine Carcinoma ◽  
Stage I ◽  
Cell Infiltration ◽  
T Cell Infiltration

e21003 Background: Pulmonary large cell neuroendocrine carcinoma (LCNCE) is a high-grade neuroendocrine tumor with poor prognosis. The genomic profile and immune feature of LCNEC have been reported in many studies. However, the relationship between immune microenvironment and the prognosis of LCNEC patients is poorly understood. Our study was aimed to examine the infiltration of CD8+ T cell and PD-L1+ cells in LCNEC patients, and explore whether CD8+T cell and PD-L1+ cells are related to LCNEC patients’ prognosis. Methods: 37 eligible LCNEC patients (stage I-III) with received the treatment of surgical operation (27 among 37 patients underwent adjuvant radiochemotherapy) were included, tumor tissues were collected from the first medical center of Chinese PLA General Hospital. Multiplex immunohistochemistry (Multi IHC) was performed using the antibodies of CD8 and PD-L1. The univariate and multivariate cox proportional hazards analyses were used to assess the association between the abundance of CD8+T cell and PD-L1+ cells with the clinical outcome of LCNEC patients. Results: Patients were divided into high and low group using the median positive percentage of CD8 or PD-L1 as cutoff. The univariate analysis showed that patients with stromal high CD8+ T cell infiltration or stage I had significantly longer disease free survival (DFS) (CD8, p = 0.03; stage I, p = 0.036), and patients with high PD-L1 expression in stroma region, I stage, adjvant radiochemotherapy had notably increased overall survival (OS) (p = 0.049, p = 0.031, p = 0.023, respectively). However, the infiltration of CD8+ T cell or PD-L1 expression in total or tumor region had no correlation with survival of LCNEC patients. Furthermore, multivariate analysis demonstrated that low CD8+ T cell density in stroma region was an independent risk factor for PFS (p = 0.03), advanced TNM stage (II-III stage, p = 0.0009) and low stromal PD-L1 expression were independent risk factors for OS (p = 0.013). Conclusions: High infiltration of CD8+ T cell or PD-L1+ cell in stroma region were independent good prognosis factors of LCNEC patients. However, these findings need a larger LCNEC cohort to validate.

scholarly journals New Artificial Intelligence Score and Immune Infiltrates as Prognostic Factors in Colorectal Cancer With Brain Metastases

2021 ◽  
Vol 12 ◽  
Author(s):  
Violaine Randrian ◽  
Amandine Desette ◽  
Sheik Emambux ◽  
Valentin Derangere ◽  
Pauline Roussille ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Prognostic Factors ◽  
T Cell ◽  
Brain Metastases ◽  
Locally Advanced ◽  
Cell Infiltration ◽  
Rectal Tumors ◽  
Tissue Micro Array ◽  
Primary Tumors ◽  
T Cell Infiltration

Incidence of brain metastases has increased in patients with colorectal cancer (CRC) as their survival has improved. CD3 T-cells and, lately, DGMate (DiGital tuMor pArameTErs) score, have been identified as prognostic factors in locally advanced CRC. Until now, there is no data concerning the prognostic value of these markers in patients with CRC-derived brain metastases. All consecutive patients with CRC-derived brain metastases diagnosed between 2000 and 2017 were retrospectively included. Staining for CD3, CD8, PD-1, PD-L1 and DGMate analyses were performed using tissue micro-array from primary tumors and, if available, brain metastases. All in all, 83 patients were included with 80 primary tumor samples and 37 brain metastases samples available. CD3 and CD8 T-cell infiltration was higher in primary tumors compared to brain metastases. We observed a significant higher DGMate score in rectal tumors compared to colon tumors (p=0.03). We also noted a trend of higher CD3 T-cell infiltration in primary tumors when brain metastases were both supra and subtentorial compared to brain metastases that were only subtentorial or supratentorial (p=0.36 and p=0.03, respectively). No correlation was found between CD3 or CD8 infiltration or DGMate score in primary tumors or brain metastases and overall survival (OS) in the overall population. In patients with rectal tumors, a high DGMate score in brain metastases was associated with longer OS (13.4 ± 6.1 months versus 6.1 ± 1.4 months, p=0.02). High CD3 T-cell infiltration in brain metastases was associated with lower OS in patients with supratentorial brain metastases (9.8 ± 3.3 months versus 16.7 ± 5.9 months, p=0.03). PD-L1 overexpression was rare, both in primary tumors and brain metastases, but PD-L1 positive primary tumors were associated with worse OS (p=0.01). In contrast to breast and lung cancer derived brain metastases, CD3 and CD8 infiltration and DGMate score are not major prognostic factors in patients with CRC-derived brain metastases.

scholarly journals Immune dysregulation underpins radioresistance in nasopharyngeal carcinoma (NPC).

2019 ◽  
Vol 5 (suppl) ◽  
pp. 52-52
Author(s):  
Hai-Tao Wang ◽  
Eugenia Li Ling Yeo ◽  
Jacqueline Seok Gek Hwang ◽  
Gek San Tan ◽  
Enya Hui Wen Ong ◽  
...  
Keyword(s):  
T Cell ◽  
De Novo ◽  
Disease Recurrence ◽  
Immune Dysregulation ◽  
Interferon Γ ◽  
Cell Infiltration ◽  
Low Frequencies ◽  
T Cell Infiltration ◽  
Whole Exome

52 Background: Radiotherapy (RT) is a primary modality in the treatment of NPC. However, 30% of patients present with disease recurrence following RT of this radiosensitive tumor. Here, we investigated the molecular and immune profiles associated with radioresistant (RR) NPC. Additionally, we investigated for aberrant molecular pathways in paired recurrences of patients to uncover new drivers underpinning radioresistance. Methods: We prospectively recruited a cohort of 100 NPC patients who completed definitive RT/chemoRT; including 30 cases who were recruited at recurrence. Whole exome sequencing (WES) at 200x was performed to identify low frequencies ( < 1%) of true somatic nucleotide variants (SNVs) and copy number alterations (CNAs). Transcriptomic profiles from RNAseq were interrogated using supervised and unsupervised statistical approaches to determine aberrant pathways that were significantly associated with RR. Results: Genomic instabilityas characterized by percentage genome alteration (PGA) was comparable in our cohort. Additionally, we did not observe any common or exclusive CNAs between RR- and nr-NPC cases. Based on a constellation of immune-related signatures, we observed an “immune-cold” profile that is associated with RR-NPC compared to nr-NPC controls, which is characterized by low expression of CD8+ T cell infiltration and interferon-γ response. Expectedly, pathways relating to angiogenesis, hypoxia and NOTCH signaling were upregulated in the RR-NPC cohort. Interestingly, we observed a reversal of the immune phenotype from “cold” to an enrichment of effector T cell infiltration in the paired recurrences. Conclusions: Here, we present a comprehensive mutational landscape of RR-NPC, which revealed the potential role of the immune environment in modulating RR. The longitudinal immune dysregulation of the tumor microenvironment between the de novo tumors and recurrences could be a driver or passenger event during the onset of recurrence.

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