scholarly journals Spatial immunoprofiling of the intratumoral and peritumoral tissue of renal cell carcinoma patients

2021 ◽  
Author(s):  
Oscar Brück ◽  
Moon Hee Lee ◽  
Riku Turkki ◽  
Ilona Uski ◽  
Patrick Penttilä ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Overall Survival ◽  
T Cells ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Immune Cell ◽  
The Cancer Genome Atlas ◽  
Poor Overall Survival ◽  
Clinicopathologic Characteristics ◽  
Peritumoral Tissue

AbstractWhile the abundance and phenotype of tumor-infiltrating lymphocytes are linked with clinical survival, their spatial coordination and its clinical significance remain unclear. Here, we investigated the immune profile of intratumoral and peritumoral tissue of clear cell renal cell carcinoma patients (n = 64). We trained a cell classifier to detect lymphocytes from hematoxylin and eosin stained tissue slides. Using unsupervised classification, patients were further classified into immune cold, hot and excluded topographies reflecting lymphocyte abundance and localization. The immune topography distribution was further validated with The Cancer Genome Atlas digital image dataset. We showed association between PBRM1 mutation and immune cold topography, STAG1 mutation and immune hot topography and BAP1 mutation and immune excluded topography. With quantitative multiplex immunohistochemistry we analyzed the expression of 23 lymphocyte markers in intratumoral and peritumoral tissue regions. To study spatial interactions, we developed an algorithm quantifying the proportion of adjacent immune cell pairs and their immunophenotypes. Immune excluded tumors were associated with superior overall survival (HR 0.19, p = 0.02) and less extensive metastasis. Intratumoral T cells were characterized with pronounced expression of immunological activation and exhaustion markers such as granzyme B, PD1, and LAG3. Immune cell interaction occurred most frequently in the intratumoral region and correlated with CD45RO expression. Moreover, high proportion of peritumoral CD45RO+ T cells predicted poor overall survival. In summary, intratumoral and peritumoral tissue regions represent distinct immunospatial profiles and are associated with clinicopathologic characteristics.

scholarly journals Comprehensive Analysis of the Expression and Prognosis Value of Chromobox Family Members in Clear Cell Renal Cell Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Yuanyuan Zhu ◽  
Zhangya Pu ◽  
Zhenfen Li ◽  
Ying Lin ◽  
Ning Li ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Overall Survival ◽  
T Cells ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Genetic Alterations ◽  
Poor Overall Survival ◽  
Cell Renal Cell Carcinoma ◽  
Expression Levels

Clear cell renal cell carcinoma (ccRCC) accounts for 80% of all renal cancers and has a poor prognosis. Chromobox (CBX) family protein expression has been reported in a variety of human malignancies, but the roles of CBXs in ccRCC remain unclear. In this study, by using ONCOMINE, UALCAN, GEPIA, Kaplan-Meier Plotter, cBioPortal, and TIMER, we found the transcriptional levels of CBX3 and CBX4 in ccRCC tissues were significantly higher than those in normal kidney tissues, whereas the transcriptional levels of CBX1, CBX5, CBX6, and CBX7 were significantly reduced in ccRCC tissues. The promoters of CBX2, CBX3, CBX4, CBX5, CBX6, CBX7, and CBX8 were hypermethylated, whereas the CBX1 promoter was hypomethylated in ccRCC. The expression of CBX1, CBX3, CBX4, CBX5, CBX6, and CBX7 was significantly associated with clinicopathological parameters in ccRCC patients. ccRCC patients with high expression levels of CBX3, CBX4, and CBX8 and low expression levels of CBX1, CBX5, CBX6, and CBX7 showed a strong association with poor overall survival. Genetic alterations in CBXs were correlated with poor overall survival and disease-free survival in patients with ccRCC. Moreover, we found significant associations between the expression of CBXs and infiltration of immune cells (B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells). Our results provide novel insights into the development of CBX-based biomarkers and therapeutic targets for ccRCC.

scholarly journals A novel 10 glycolysis-related genes signature could predict overall survival for clear cell renal cell carcinoma

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Qianwei Xing ◽  
Tengyue Zeng ◽  
Shouyong Liu ◽  
Hong Cheng ◽  
Limin Ma ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Overall Survival ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Cox Regression ◽  
Clear Cell ◽  
Low Risk ◽  
The Cancer Genome Atlas ◽  
Regression Analyses ◽  
Cell Renal Cell Carcinoma

Abstract Background The role of glycolysis in tumorigenesis has received increasing attention and multiple glycolysis-related genes (GRGs) have been proven to be associated with tumor metastasis. Hence, we aimed to construct a prognostic signature based on GRGs for clear cell renal cell carcinoma (ccRCC) and to explore its relationships with immune infiltration. Methods Clinical information and RNA-sequencing data of ccRCC were obtained from The Cancer Genome Atlas (TCGA) and ArrayExpress datasets. Key GRGs were finally selected through univariate COX, LASSO and multivariate COX regression analyses. External and internal verifications were further carried out to verify our established signature. Results Finally, 10 GRGs including ANKZF1, CD44, CHST6, HS6ST2, IDUA, KIF20A, NDST3, PLOD2, VCAN, FBP1 were selected out and utilized to establish a novel signature. Compared with the low-risk group, ccRCC patients in high-risk groups showed a lower overall survival (OS) rate (P = 5.548Ee-13) and its AUCs based on our established signature were all above 0.70. Univariate/multivariate Cox regression analyses further proved that this signature could serve as an independent prognostic factor (all P < 0.05). Moreover, prognostic nomograms were also created to find out the associations between the established signature, clinical factors and OS for ccRCC in both the TCGA and ArrayExpress cohorts. All results remained consistent after external and internal verification. Besides, nine out of 21 tumor-infiltrating immune cells (TIICs) were highly related to high- and low- risk ccRCC patients stratified by our established signature. Conclusions A novel signature based on 10 prognostic GRGs was successfully established and verified externally and internally for predicting OS of ccRCC, helping clinicians better and more intuitively predict patients’ survival.

Neutrophil–lymphocyte ratio as a prognostic factor for survival in patients with advanced renal cell carcinoma (Turkish Oncology Group Study)

2020 ◽  
Vol 26 (7) ◽  
pp. 1583-1589
Author(s):  
Mutlu Hizal ◽  
Mehmet AN Sendur ◽  
Hatime Arzu Yasar ◽  
Kadriye Bir Yucel ◽  
Cagatay Arslan ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Overall Survival ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Kinase Inhibitors ◽  
Advanced Renal Cell Carcinoma ◽  
Study Group ◽  
Poor Overall Survival ◽  
Neutrophil Lymphocyte Ratio ◽  
Lymphocyte Ratio

Background To describe the prognostic value of neutrophil–lymphocyte ratio and its effect on survival in in patients with advanced renal cell carcinoma. Methods We retrospectively analyzed 331 patients. The cut-off value of neutrophil–lymphocyte ratio was specified as “3” which is mostly close—and also clinically easily applicable—to the median neutrophil–lymphocyte ratio level of our study group. High group is identified as neutrophil–lymphocyte ratio >3 (n = 160) and low group is identified as neutrophil–lymphocyte ratio ≤3 (n = 163). Results A total of 331 (with 211 male and 120 female) patients were enrolled to study. The median age of the patients was 58. The International Metastatic RCC Database Consortium risk score is calculated for the 72.8% (n = 241) of the study group and among these patients, favorable, intermediate, and poor risk rates were 22, 45.2, and 32.8%. The total usage of tyrosine kinase inhibitors reached 78% of the patients. The median overall survival was 32 months versus 11 months in the neutrophil–lymphocyte ratio low and high groups, respectively (HR: 0.49 (95% CI 0.37–0.65), p < 0.001). Conclusion In conclusion, the pre-treatment value of elevated neutrophil–lymphocyte ratio might be a predictor of poor overall survival in advanced renal cell carcinoma patients.

Immune cell repertoire in patients with metastatic renal cell carcinoma: Data from prospective clinical trial.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 452-452
Author(s):  
Vijay Damarla ◽  
Paul Elson ◽  
Laura S. Wood ◽  
Sylvia Sybor ◽  
Pat A. Rayman ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
T Cells ◽  
Cell Carcinoma ◽  
Systemic Therapy ◽  
Renal Cell ◽  
Immune Cell ◽  
Cell Repertoire ◽  
Immune Parameters ◽  
Lower Baseline ◽  
Metastatic Rcc

452 Background: Immune dysfunction is documented in renal cell carcinoma (RCC) patients and likely influences tumor progression. An ongoing prospective trial of observation in metastatic RCC patients prior to systemic therapy is investigating circulating immune cell populations. Methods: Asymptomatic patients with low volume metastatic disease were enrolled and followed until starting initial systemic treatment. Peripheral blood specimens were collected at baseline and again at 3, 6, 9, 12, 16, 20, and 24 months, and then every 6 months until initiating systemic therapy. Immune parameters measured included CD3+ and CD4+ INF-γ producing T cells (INF-γ+ T), CD4+CD25+FoxP3+ regulatory T-cells (Treg), CD33+HLADr-CD15+CD14- neutrophilic myeloid-derived suppressor cells (N-MDSC), monocytic M-MDSC, total MDSC, and lineage-negative MDSC. Similar immune parameters were recorded for treatment-naïve patients prior to immediate systemic therapy (sunitinib or pazopanib, n=34) and healthy volunteers (n=22) on separate IRB-approved protocols. The immune data was analyzed using Wilcoxon rank sum and signed rank tests and proportional hazards models. Results: Forty patients enrolled in the observation study had immunologic data. 25 patients (62%) started systemic therapy, and 15 (38%) continue observation. The observation group had lower baseline levels of MDSC, N-MDSC, M-MDSC, Tregs and higher levels of CD3+INF-γ+ T cells, CD4+ INF-γ+ T cells, and lineage negative MDSC compared to the immediate treatment group, although higher MDSCs and lower Tregs compared to healthy controls. The impact of baseline parameters on the duration of observation revealed that lower Tregs (p=0.003) were associated with a longer time on observation. There were no significant changes in immune parameters of observation patients over the length of observation. Conclusions: Metastatic RCC patients with indolent disease have low levels of Treg and MDSC, and a relatively preserved immune cell repertoire compared to patients requiring immediate therapy. Lower baseline Tregs may be associated with a longer length of observation.

Downregulation of ACE2 is associated with advanced pathological features and poor prognosis in clear cell renal cell carcinoma

2021 ◽  
Author(s):  
Tianjiao Wang ◽  
Fang Xie ◽  
Yun-Hui Li ◽  
Bin Liang
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Immune Cell ◽  
Clear Cell ◽  
Expression Profiles ◽  
Histological Grade ◽  
Clinical Stage ◽  
The Cancer Genome Atlas ◽  
Cell Renal Cell Carcinoma

Aims: The aim of this study was to explore the alteration in ACE2 expression and correlation between ACE2 expression and immune infiltration in clear cell renal cell carcinoma (ccRCC). Methods: The authors first analyzed the expression profiles and prognostic value of ACE2 in ccRCC patients using The Cancer Genome Atlas public database. The authors used ESTIMATE and CIBERSORT algorithms to analyze the correlation between ACE2 expression and tumor microenvironment in ccRCC samples. Results: ACE2 was correlated with sex, distant metastasis, clinical stage, tumor T stage and histological grade. Moreover, downregulation of ACE2 was correlated with unfavorable prognosis. In addition, ACE2 expression was associated with different immune cell subtypes. Conclusion: The authors' analyses suggest that ACE2 plays an important role in the development and progression of ccRCC and may serve as a potential prognostic biomarker in ccRCC patients.

Modulation of immune cell subpopulations in renal cell carcinoma patients by sunitinib.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 395-395 ◽  
Author(s):  
B. Seliger ◽  
C. Giersberg ◽  
M. D. Staehler
Keyword(s):  
Renal Cell Carcinoma ◽  
T Cells ◽  
Cell Carcinoma ◽  
Nk Cells ◽  
Renal Cell ◽  
Immune Cell ◽  
Memory T Cells ◽  
Treatment Schedule ◽  
Sunitinib Treatment ◽  
Over Time

395 Background: Increased numbers of immune suppressive cells, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSC) as well as alterations in the frequency and function of activated and memory T cells in peripheral blood mononuclear cells (PBMNC) represent immune escape mechanisms of renal cell carcinoma (RCC). The tyrosine kinase inhibitor sunitinib, which is currently successfully implemented in the treatment of RCC has been shown to modulate immune suppressive cells as well as T lymphocytes thereby shifting the immune balance in these patients to a more stimulating setting. Methods: Using flow cytometry and a large panel of antibodies directed against different immunomodulatory molecules, we here analysed the effects of (i) adjuvant sunitinib treatment (50 mg for 4 weeks, on 2 weeks off) on the composition of various immune cell populations, their function and activity in RCC patients and (ii) sunitinib treatment of PBMNC from healthy donors over time Results: A time-dependent decrease in the frequency of Treg and MDSC was found in PBMNCs during in vitro and in vivo sunitinib treatment. In addition, the number of NK cells, activated and/or memory T cells was increased in PBMNC of TKI-treated patients over time. Conclusions: This observation may have important implications for (i) the monitoring of the sunitinib activity on immune cells, (ii) the treatment schedule including duration of TKI therapy, and (iii) the implementation of sunitinib in combination with immunotherapies in RCC patients. Long-term monitoring of a larger patients' group will show whether the activation of T cells and NK cells as well as the decrease of immune suppressive cells due to sunitinib treatment is associated with enhanced antitumor responses. [Table: see text]

The immune landscape of renal cell carcinoma and its association with intratumoral clonality.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 605-605
Author(s):  
Andrew G. Winer ◽  
Yasin Senbabaoglu ◽  
Ron Gejman ◽  
Irina Ostrovnaya ◽  
Samuel D. Kaffenberger ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
T Cell ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Immune Cell ◽  
The Cancer Genome Atlas ◽  
Data Sets ◽  
Cell Renal Cell Carcinoma ◽  
Immune Infiltration ◽  
T Cell Infiltration

605 Background: Clear cell renal cell carcinoma (ccRCC) is among the most highly infiltrated tumors despite a relatively low mutation burden. Despite success in treating subsets of these patients with immunotherapy, the high immune-infiltration of ccRCC remains a conundrum that has not been sufficiently addressed. Methods: We utilized an original RNAseq-based aggregate immune score (Senbabaoglu Y, bioRxiv, 2015) to compare immune infiltration levels across 20 tumor types profiled in The Cancer Genome Atlas (TCGA) and validated our results with an independent cohort of ccRCC patients (Sato Y, Nat Genet, 2013). We also evaluated the immunogenic effect of intratumoral heterogeneity (ITH) through an analysis of clonal architecture in ccRCC tumors from both of the aforementioned data sets using the SciClone (Miller C, PLoS Comput Biol, 2014) algorithm. Results: We identified ccRCC as an immunogenic outlier that is unique from other highly infiltrated tumors in its exceptional overexpression of antigen presentation machinery compared to normal tissue. In a focused decomposition of immune cell levels within the 415 ccRCC tumors from TCGA, three unique clusters of tumors emerged primarily separated by varying degrees of T cell infiltration; termed (1) T-cell-enriched, (2) heterogeneous, and (3) non-infiltrated groups. These clusters were validated in an independent ccRCC cohort of 101 patients. A comparison of the degree of clonality with immune infiltration levels revealed that tumors with less ITH (i.e. fewer subclones) had significantly higher immune infiltration in both the TCGA and the validation cohort . Conclusions: Our findings provide novel insight into the immune landscape of ccRCC tumors and explore a potential mechanism for the immunogenicity of these tumors. Such information can potentially be used to aid in predicting therapeutic response to immunomodulatory agents.

Higher circulating expression levels of miR-221 associated with poor overall survival in renal cell carcinoma patients

Tumor Biology ◽  
2013 ◽  
Vol 35 (5) ◽  
pp. 4057-4066 ◽  
Author(s):  
Ana L. Teixeira ◽  
Marta Ferreira ◽  
Joana Silva ◽  
Mónica Gomes ◽  
Francisca Dias ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Overall Survival ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Poor Overall Survival ◽  
Expression Levels

scholarly journals Epigenetic signature predicts overall survival clear cell renal cell carcinoma

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Yejinpeng Wang ◽  
Liang Chen ◽  
Lingao Ju ◽  
Kaiyu Qian ◽  
Xinghuan Wang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Renal Cell Carcinoma ◽  
Overall Survival ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Cox Regression ◽  
Clear Cell ◽  
The Cancer Genome Atlas ◽  
Cell Renal Cell Carcinoma ◽  
Cox Regression Analysis

Abstract Background Recently, increasing study have found that DNA methylation plays an important role in tumor, including clear cell renal cell carcinoma (ccRCC). Methods We used the DNA methylation dataset of The Cancer Genome Atlas (TCGA) database to construct a 31-CpG-based signature which could accurately predict the overall survival of ccRCC. Meanwhile, we constructed a nomogram to predict the prognosis of patients with ccRCC. Result Through LASSO Cox regression analysis, we obtained the 31-CpG-based epigenetic signature which were significantly related to the prognosis of ccRCC. According to the epigenetic signature, patients were divided into two groups with high and low risk, and the predictive value of the epigenetic signature was verified by other two sets. In the training set, hazard ratio (HR) = 13.0, 95% confidence interval (CI) 8.0–21.2, P < 0.0001; testing set: HR = 4.1, CI 2.2–7.7, P < 0.0001; entire set: HR = 7.2, CI 4.9–10.6, P < 0.0001, Moreover, combined with clinical indicators, the prediction of 5-year survival of ccRCC reached an AUC of 0.871. Conclusions Our study constructed a 31-CpG-based epigenetic signature that could accurately predicted overall survival of ccRCC and staging progression of ccRCC. At the same time, we constructed a nomogram, which may facilitate the prediction of prognosis for patients with ccRCC.

scholarly journals CCR5 blockade inflames antitumor immunity in BAP1-mutant clear cell renal cell carcinoma

2020 ◽  
Vol 8 (1) ◽  
pp. e000228
Author(s):  
Quan Zhou ◽  
Yangyang Qi ◽  
Zewei Wang ◽  
Han Zeng ◽  
Hongyu Zhang ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
T Cells ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
The Cancer Genome Atlas ◽  
In Vivo Studies ◽  
Cell Renal Cell Carcinoma ◽  
Ccr5 Blockade

BackgroundPatients with BRCA1-associated protein 1 (BAP1)-mutant clear cell renal cell carcinoma (ccRCC) have worse prognosis. C-C chemokine receptor 5 (CCR5) plays an important role in ccRCC development and its expression is elevated in BAP1-mutant tumors.Methods533 patients with ccRCC from The Cancer Genome Atlas cohort and 797 patients with ccRCC from the Shanghai cohort were enrolled. In vitro and in vivo studies were conducted with human ccRCC tumors and murine tumor models. The association between BAP1 and CCR5 or its ligands was assessed by immunohistochemistry, flow cytometry, real-time PCR and ELISA. Survival was compared between different subpopulations of patients using Kaplan-Meier curve. Therapeutic effect of CCR5 blockade was validated using human ccRCC tumors and murine models.ResultsExpression of CCR5 and its ligands were elevated in BAP1-mutant patients with ccRCC. High CCR5 expression was indicative of poor prognosis in BAP1-low group of patients. CCR5 blockade prolonged the survival of tumor-bearing mice, resulting in enhanced cytotoxicity of T cells and antigen presentation of dendritic cells but repressed immune checkpoint expression. CCR5 ligands could recruit CCR5+regulatory T cells to the tumor microenvironment. Additionally, BAP1-mutant ccRCC tumor cells secreted CCR5 ligands, which increased programmed cell death ligand 1 expression. However, both processes could be inhibited by CCR5 blockade. Study limitations include the unclear impact of CCR5 expressed by other cell populations.ConclusionsCCR5 in BAP1-mutant ccRCC results in an immune-suppressive microenvironment. Targeting CCR5 could provide a potential therapeutic benefit for patients.Trial registration numberNCT01358721, CA209-009.

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