Dataset Information

Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma.

ABSTRACT: Immune checkpoint inhibitors targeting the programmed cell death 1 receptor (PD-1) improve survival in a subset of patients with clear cell renal cell carcinoma (ccRCC). To identify genomic alterations in ccRCC that correlate with response to anti-PD-1 monotherapy, we performed whole-exome sequencing of metastatic ccRCC from 35 patients. We found that clinical benefit was associated with loss-of-function mutations in the PBRM1 gene (P = 0.012), which encodes a subunit of the PBAF switch-sucrose nonfermentable (SWI/SNF) chromatin remodeling complex. We confirmed this finding in an independent validation cohort of 63 ccRCC patients treated with PD-1 or PD-L1 (PD-1 ligand) blockade therapy alone or in combination with anti-CTLA-4 (cytotoxic T lymphocyte-associated protein 4) therapies (P = 0.0071). Gene-expression analysis of PBAF-deficient ccRCC cell lines and PBRM1-deficient tumors revealed altered transcriptional output in JAK-STAT (Janus kinase-signal transducers and activators of transcription), hypoxia, and immune signaling pathways. PBRM1 loss in ccRCC may alter global tumor-cell expression profiles to influence responsiveness to immune checkpoint therapy.

SUBMITTER: Miao D

PROVIDER: S-EPMC6035749 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma.

Miao Diana D Margolis Claire A CA Gao Wenhua W Voss Martin H MH Li Wei W Martini Dylan J DJ Norton Craig C Bossé Dominick D Wankowicz Stephanie M SM Cullen Dana D Horak Christine C Wind-Rotolo Megan M Tracy Adam A Giannakis Marios M Hodi Frank Stephen FS Drake Charles G CG Ball Mark W MW Allaf Mohamad E ME Snyder Alexandra A Hellmann Matthew D MD Ho Thai T Motzer Robert J RJ Signoretti Sabina S Kaelin William G WG Choueiri Toni K TK Van Allen Eliezer M EM

Science (New York, N.Y.) 20180104 6377

Immune checkpoint inhibitors targeting the programmed cell death 1 receptor (PD-1) improve survival in a subset of patients with clear cell renal cell carcinoma (ccRCC). To identify genomic alterations in ccRCC that correlate with response to anti-PD-1 monotherapy, we performed whole-exome sequencing of metastatic ccRCC from 35 patients. We found that clinical benefit was associated with loss-of-function mutations in the <i>PBRM1</i> gene (<i>P</i> = 0.012), which encodes a subunit of the PBAF s ...[more]

PMID: 29301960

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Project description:Background: It is anticipated that there will be a large rise in the number of tumor diagnoses and mortality in those aged 65 and older over the course of upcoming decades. Immune checkpoint inhibitors, often known as ICIs, boost immune system activity by selectively targeting ICI genes. On the other hand, old age may be connected with unfavorable results. Methods: The Cancer Genome Atlas (TCGA) provided gene expression data from ccRCC tissue and key clinical variables. ICI gene databases were applied and verified using the GEO database. Results: We identified 14 ICI genes as risk gene signatures among 528 ccRCC patients using univariate and multivariable cox hazard models, and the elderly group was linked with poor survival. Then, by utilizing a new nomogram method, the TNFSF15 gene and age predicting values were estimated at one, three, and five years (85%, 81%, and 81%), respectively, and our age-related risk score was significant even after multivariable analysis (HR = 1.518, p = 0.009, CI = 1.1102.076). TNFSF15 gene expression was lower in elderly ccRCC patients (p = 0.0001). A negative connection between age and the TNFSF15 gene expression was discovered by correlation analysis (p = 0.0001). The verification of the gene by utilizing GEO (GSE167093) with 604 patients was obtained as external validation that showed significant differences in the TNFSF15 gene between young and elderly patients (p = 0.007). Additionally, the protein-protein interactions of the TNFSF15 gene with other ICI genes and aging-related genes was determined. In addition, the TNFSF15 expression was significantly correlated with pathological stages (p = 0.018). Furthermore, it was discovered that the biological processes of senescence, cellular senescence, the immune system, and many immune cell infiltration and immune function types are all closely tied. Conclusions: Along with the risk score evaluation, the ICI gene TNFSF15 was identified as a tumor suppressor gene related to inequalities in age survival and is associated with pathological stages and different immunity statuses. The aging responses of ccRCC patients and related gene expression need further investigation in order to identify potential therapeutic targets.

Project description:BackgroundImmune checkpoint inhibitor (ICI) treatment has enhanced survival outcomes in clear cell renal cell carcinoma (ccRCC) patients. Nevertheless, the effectiveness of immunotherapy in ccRCC patients is restricted and we intended to develop and characterize an immune response prediction signature (IRPS) to forecast the efficacy of immunotherapy.MethodsRNA-seq expression profile and clinicopathologic characteristics of 539 kidney cancer and 72 patients with normal specimens, were downloaded from the Cancer Genome Atlas (TCGA) database, while the Gene Expression Omnibus (GEO) database was used as the validation set, which included 24 ccRCC samples. Utilization of the TCGA data and immune genes databases (ImmPort and the InnateDB), we explored through Weighted Gene Co-expression Network Analysis (WGCNA), along with Least Absolute Shrinkage and Selection Operator method (LASSO), and constructed an IRPS for kidney cancer patients. GSEA and CIBERSORT were performed to declare the molecular and immunologic mechanism underlying the predictive value of IRPS. The Human Protein Atlas (HPA) was deployed to verify the protein expressions of IRPS genes. Tumor immune dysfunction and exclusion (TIDE) score and immunophenoscore (IPS) were computed to determine the risk of immune escape and value the discrimination of IRPS. A ccRCC cohort with anti-PD-1 therapy was obtained as an external validation data set to verify the predictive value of IRPS.ResultsWe constructed a 10 gene signature related to the prognosis and immune response of ccRCC patients. Considering the IRPS risk score, patients were split into high and low risk groups. Patients with high risk in the TCGA cohort tended towards advanced tumor stage and grade with poor prognosis (p < 0.001), which was validated in GEO database (p = 0.004). High-risk group tumors were related with lower PD-L1 expression, higher TMB, higher MSIsensor score, lower IPS, higher TIDE score, and enriched Treg cells, which might be the potential mechanism of immune dysfunction and exclusion. Patients in the IRPS low risk group had better PFS (HR:0.73; 95% CI: 0.54-1.0; P = 0.047).ConclusionA novel biomarker of IRPS was constructed to predict the benefit of immunotherapy, which might lead to more individualized prognoses and tailored therapy for kidney cancer patients.

Dataset Information

Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma.

Publications

Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma.

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