scholarly journals Determinants of anti-PD1 response and resistance in clear cell renal cell carcinoma

2021 ◽  
Author(s):  
Lewis Au ◽  
Emine Hatipoglu ◽  
Marc Robert de Massy ◽  
Kevin Litchfield ◽  
Andrew Rowan ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
T Cells ◽  
Cell Carcinoma ◽  
Cd8 T Cells ◽  
Renal Cell ◽  
Clear Cell ◽  
Endogenous Retrovirus ◽  
Human Endogenous Retrovirus ◽  
Cell Renal Cell Carcinoma ◽  
Pre Treatment

Antigen recognition and T-cell mediated cytotoxicity in clear-cell renal cell carcinoma (ccRCC) remains incompletely understood. To address this knowledge gap, we analysed 115 multiregion tumour samples collected from 15 treatment-naive patients pre- and post-nivolumab therapy, and at autopsy in three patients. We performed whole-exome sequencing, RNAseq, TCRseq, multiplex immunofluorescence and flow cytometry analyses and correlated with clinical response. We observed pre-treatment intratumoural TCR clonal expansions suggesting pre-existing immunity. Nivolumab maintained pre-treatment expanded, clustered TCR clones in responders, suggesting ongoing antigen-driven stimulation of T-cells. T-cells in responders were enriched for expanded TCF7+CD8+ T-cells and upregulated GZMK/B upon nivolumab-binding. By contrast, nivolumab promoted accumulation of new TCR clones in non-responders, replacing pre-treatment expanded clonotypes. In this dataset, mutational features did not correlate with response to nivolumab and human endogenous retrovirus expression correlated indirectly. Our data suggests that nivolumab potentiates clinical responses in ccRCC by binding pre-existing expanded CD8+ T-cells to enhance cytotoxicity.

Tumor-infiltrating CD8+ T cells recognize a heterogeneously expressed functional neoantigen in clear cell renal cell carcinoma

2021 ◽  
Author(s):  
Masahiro Matsuki ◽  
Yoshihiko Hirohashi ◽  
Munehide Nakatsugawa ◽  
Aiko Murai ◽  
Terufumi Kubo ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
T Cells ◽  
Cell Carcinoma ◽  
Cd8 T Cells ◽  
Renal Cell ◽  
Clear Cell ◽  
Cell Renal Cell Carcinoma

Tumor infiltrating and peripheral CD4+ILT2+ T cells are a cytotoxic subset selectively inhibited by HLA-G in clear cell renal cell carcinoma patients

2021 ◽  
Author(s):  
Alix Jacquier ◽  
Tiphaine Lambert ◽  
Jean-François Delattre ◽  
Malika Djouadou ◽  
Jérôme Vérine ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
T Cells ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Cell Renal Cell Carcinoma

Systematic Analyses of The Role of Prognostic And Immunological of EIF3A, A Reader Protein, In Clear Cell Renal Cell Carcinoma

2021 ◽  
Author(s):  
Yi Zhang ◽  
Xiaoliang Hua ◽  
Haoqiang Shi ◽  
Li Zhang ◽  
HaiBing Xiao ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
T Cells ◽  
Cell Carcinoma ◽  
Immune Cells ◽  
Renal Cell ◽  
Clear Cell ◽  
Multivariate Analyses ◽  
Enrichment Analysis ◽  
Marker Genes ◽  
Cell Renal Cell Carcinoma

Abstract Background: Eukaryotic initiation factor 3a, EIF3A, as a “reader” protein for RNA methylation, has been found to be related to promote tumorigenesis in different variety of cancers. The impaction of EIF3A in clear cell renal cell carcinoma (ccRCC) has yet to be expounded. This study aimed to identify the prognostic value of EIF3A in ccRCC and investigate the relationship between expression and immune infiltration.Methods: We collected 29 m6a related mRNA data and clinicopathological parameters from Cancer Genmoe Atlas (TCGA) database. Logistic regression analyses were used to analyze the correlation between EIF3A expression and clinical characteristics. Immunohistochemistry (IHC) were applied to examine EIF3A levels in normal and ccRCC tissues. Univariate and multivariate analyses were conducted to recognize forcefully independent factor in associated with overall survival (OS) and diseases free survival (DFS). Nomogram was aim at predicting the 1-, 3-and 5-year survival probabilities. Gene set enrichment analysis (GSEA) was carried out to the potential function and related signaling pathways of EIF3A expression. To investigate EIF3A of co-expressed genes, we used LinkedOmics and its result was undertaken enrichment analysis. Simultaneously, to employ LinkedOmics and STRING dataset drew a conclusion that EIF3A co-expressed genes and visualized via Cytoscape. Finally, we evaluated that EIF3A expression correlated between with infiltration of immune cells and the expression of marker genes in ccRCC by Tumor Immune Estimation Resource (TIMER) and Gene Expression Profiling Interactive Analysis (GEPIA).Result: EIF3A expression was significantly different between ccRCC tissues and normal tissues. EIF3A expression was connected with poor prognostic clinicopathological factors, and K–M analyses revealed that low EIF3A expression was correlated with poor prognosis. The result of univariate and multivariate analyses proved that EIF3A was a prognostic factor in ccRCC patients. GSEA results indicated that high expression was enriched in renal cell carcinoma pathway and so on. EIF3A expression was significantly positively correlated with B cells, CD8+T cells, CD4+T cells, neutrophils, macrophages, and dendritic cells. Furthermore, EIF3A expression was associated with most of marker genes of immune cells.Conclusions: EIF3A could serve as potential biomarkers for prognostic and diagnostic stratification factor for ccRCC and is related with immune cells infiltrates.

scholarly journals Tumor-Infiltrating T Cells From Clear Cell Renal Cell Carcinoma Patients Recognize Neoepitopes Derived From Point and Frameshift Mutations

2020 ◽  
Vol 11 ◽  
Author(s):  
Ulla Kring Hansen ◽  
Sofie Ramskov ◽  
Anne-Mette Bjerregaard ◽  
Annie Borch ◽  
Rikke Andersen ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
T Cells ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Cell Renal Cell Carcinoma ◽  
Frameshift Mutations

scholarly journals A Novel Immune-Related lncRNA-Based Model for Survival Prediction in Clear Cell Renal Cell Carcinoma

2021 ◽  
Vol 2021 ◽  
pp. 1-37
Author(s):  
Zedan Zhang ◽  
Yanlin Tang ◽  
Yanjun Liu ◽  
Hongkai Zhuang ◽  
Enyu Lin ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
T Cells ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Cox Regression ◽  
Clear Cell ◽  
Functional Enrichment ◽  
Clinical Parameters ◽  
Training Set ◽  
Cell Renal Cell Carcinoma

Background. Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer whose incidence and mortality rate are increasing. Identifying immune-related lncRNAs and constructing a model would probably provide new insights into biomarkers and immunotherapy for ccRCC and aid in the prognosis prediction. Methods. The transcription profile and clinical information were obtained from The Cancer Genome Atlas (TCGA). Immune-related gene sets and transcription factor genes were downloaded from GSEA website and Cistrome database, respectively. Tumor samples were divided into the training set and the testing set. Immune-related differentially expressed lncRNAs (IDElncRNAs) were identified from the whole set. Univariate Cox regression, LASSO, and stepwise multivariate Cox regression were performed to screen out ideal prognostic IDElncRNAs (PIDElncRNAs) from the training set and develop a multi-lncRNA signature. Results. Consequently, AC012236.1, AC078778.1, AC078950.1, AC087318.1, and AC092535.4 were screened to be significantly related to the prognosis of ccRCC patients, which were used to establish the five-lncRNA signature. Its wide diagnostic capacity was revealed in different subgroups of clinical parameters. Then AJCC-stage, Fuhrman-grade, pharmaceutical, age, and risk score regarded as independent prognostic factors were integrated to construct a nomogram, whose good performance in predicting 3-, 5-, and 7-year overall survival of ccRCC patients was revealed by time-dependent ROC curves and verified by the testing sets and ICGC dataset. The calibration plots showed great agreement of the nomogram between predicted and observed outcomes. Functional enrichment analysis showed the signature and each lncRNA were mainly enriched in pathways associated with regulation of immune response. Several kinds of tumor-infiltrating immune cells like regulatory T cells, T follicular helper cells, CD8+ T cells, resting mast cells, and naïve B cells were significantly correlated with the signature. Conclusion. Therefore, we constructed a five-lncRNA model integrating clinical parameters to help predict the prognosis of ccRCC patients. The five immune-related lncRNAs could potentially be therapeutic targets for immunotherapy in ccRCC in the future.

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