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Chromosome 9p copy number gains involving PD-L1 are associated with a specific proliferation and immune-modulating gene expression program active across major cancer types.

ABSTRACT: Inhibition of the PD-L1/PD-1 immune checkpoint axis represents one of the most promising approaches of immunotherapy for various cancer types. However, immune checkpoint inhibition is successful only in subpopulations of patients emphasizing the need for powerful biomarkers that adequately reflect the complex interaction between the tumor and the immune system. Recently, recurrent copy number gains (CNG) in chromosome 9p involving PD-L1 were detected in many cancer types including lung cancer, melanoma, bladder cancer, head and neck cancer, cervical cancer, soft tissue sarcoma, prostate cancer, gastric cancer, ovarian cancer, and triple-negative breast cancer.Here, we applied functional genomics to analyze global mRNA expression changes associated with chromosome 9p gains. Using the TCGA data set, we identified a list of 75 genes that were strongly up-regulated in tumors with chromosome 9p gains across many cancer types.As expected, the gene set was enriched for chromosome 9p and in particular chromosome 9p24 (36 genes and 23 genes). Furthermore, we found enrichment of two expression programs derived from genes within and beyond 9p: one implicated in cell cycle regulation (22 genes) and the other implicated in modulation of the immune system (16 genes). Among these were specific cytokines and chemokines, e.g. CCL4, CCL8, CXCL10, CXCL11, other immunoregulatory genes such as IFN-G and IDO1 as well as highly expressed proliferation-related kinases and genes including PLK1, TTK, MELK and CDC20 that represent potential drug targets.Collectively, these data shed light on mechanisms of immune escape and stimulation of proliferation in cancer with PD-L1 CNG and highlight additional vulnerabilities that may be therapeutically exploitable.

SUBMITTER: Budczies J

PROVIDER: S-EPMC5719741 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Chromosome 9p copy number gains involving PD-L1 are associated with a specific proliferation and immune-modulating gene expression program active across major cancer types.

Budczies Jan J Budczies Jan J Denkert Carsten C Győrffy Balázs B Schirmacher Peter P Stenzinger Albrecht A

BMC medical genomics 20171206 1

<h4>Background</h4>Inhibition of the PD-L1/PD-1 immune checkpoint axis represents one of the most promising approaches of immunotherapy for various cancer types. However, immune checkpoint inhibition is successful only in subpopulations of patients emphasizing the need for powerful biomarkers that adequately reflect the complex interaction between the tumor and the immune system. Recently, recurrent copy number gains (CNG) in chromosome 9p involving PD-L1 were detected in many cancer types inclu ...[more]

PMID: 29212506

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Project description:Cervical cancer has become a leading cause of death in both HIV-infected and uninfected women. Previous studies have revealed that antiretroviral therapy (ART) possesses anti-human papillomavirus (HPV) and antitumour properties, potentially serving as an anticancer agent and improving functional immunity in HIV-positive individuals. However, to the best of our knowledge, no studies have examined the association between ART and the clinical outcome of patients with pre-existing invasive cervical cancer. The current study analysed 48 HIV-positive and 123 HIV-negative patients with locally advanced stage IB2-IVA cervical cancer between December 2008 and December 2016. Tumours were categorized based on programmed cell death-ligand 1 (PD-L1) immunoreactivity and copy number alterations in the PD-L1 gene, as determined by fluorescence in situ hybridization. The results revealed that ART-treated patients exhibited a lower prevalence of PD-L1 immunopositivity, PD-L1 amplification and polysomy compared with patients that did not receive ART and those that were HIV-negative. Furthermore, ART-treated patients with PD-L1 immunonegativity exhibited an improved recurrence-free survival (RFS) compared with patients that did not receive ART and HIV-negative individuals with PD-L1 immunopositivity (P=0.041 vs. P=0.030). Additionally, ART-exposed patients with PD-L1 disomy demonstrated improved locoregional recurrence-free survival (LRR) when compared with HIV-negative patients with PD-L1 amplification and polysomy (P=0.039 vs. P=0.007), RFS (P<0.001 vs. P=0.006) and cancer-specific survival (CSS) (P=0.021 vs. P=0.025). ART-exposed patients with PD-L1 disomy also exhibited improved RFS (P<0.001) and CSS (P<0.001) compared with HIV-negative patients with PD-L1 amplification. Improved LRRs were demonstrated in ART-exposed patients with PD-L1 disomy (P=0.028) compared with non-HIV patients with polysomy. Following multivariate analysis, International Federation of Gynaecology and Obstetrics stage and PD-L1 amplification were determined to be predictors of poor a RFS [hazard ratio (HR), 2.43; 95% confidence interval (CI), 1.37-4.30; P=0.002 vs. HR, 7.03; 95% CI, 2.79-17.74; P<0.001) and CSS (HR, 11.47; 95% CI, 4.70-27.99; P<0.001 vs. HR, 4.05; 95% CI, 1.64-9.98; P=0.002). However, only PD-L1 polysomy was determined to be a predictor of poor LRR (HR, 2.50; 95% CI, 1.11-5.63; P=0.027). HIV status was not associated with poor outcomes, as determined using Cox models. The results of the current study indicated that ART may be used for the treatment of cervical cancer in both HIV-infected and uninfected patients. However, additional research is required to further elucidate these results.

Dataset Information

Chromosome 9p copy number gains involving PD-L1 are associated with a specific proliferation and immune-modulating gene expression program active across major cancer types.

Publications

Chromosome 9p copy number gains involving PD-L1 are associated with a specific proliferation and immune-modulating gene expression program active across major cancer types.

Similar Datasets

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