Abstract
BackgroundPoly (ADP-ribose) polymerases-1 (PARP1) alterations are associated with PARP1 inhibitor resistance, regulating the function of Treg cells and PDL1 expression in tumor cells, and high PARP1 expression is significantly associated with aggressive behavior and chemotherapeutic resistance in several tumors. However, a comprehensive analysis of the predictive values of PARP1 alteration for immune checkpoint inhibitor (ICI) effectiveness in tumors remains unclear, and the associations between its expression and immunotherapy signatures also needs to be explored further.MethodsWe performed some analyses with the cBioPortal online database (https://www.cbioportal.org), TIMER2.0 (Tumor Immune Estimation Resource 2.0, http://timer.comp-genomics.org/) and TCGA database (https://xenabrowser.net or https://portal.gdc.cancer.gov/). Survival analysis was conducted using Kaplan–Meier method, and the associations between PARP1 transcription levels and immune checkpoint gene expression, the number of neoantigens, tumor mutation burden (TMB) levels, and microsatellite instability (MSI) event are analyzed by spearman correlation analysis and visualization of those mentioned above is performed using R, version 3.6.3 (http://www.r-project.org/).ResultsWe found that PARP1 was altered in 1338 (2.9%) out of 45604 patients with diverse tumors, which was associated with markedly higher TMB levels in a variety of tumors (P < 0.01). Impressively, patients with PARP1 alterations in advanced tumors showed better overall survival (OS) in the ICI-treated cohort (P = 0.016). PARP1 altered group was substantially correlated with higher immune infiltrates across most tumors, including CD8+ T cells in colorectal adenocarcinoma (P = 0.0061), endometrial carcinoma (P = 0.0033), stomach cancer (P = 0.033), and cervical cancer (P = 0.026), respectively. The PARP1 altered group showed high expression in transcription (P < 0.001), and higher expression of LAG3, PDCD1, CTLA-4, and TIGIT (P < 0.05). Higher PARP1 expression was present in 27 tumor compared the corresponding normal tissues using the GTEx and TCGA databases and it had a worse OS in several tumors (P < 0.05). Further, high PARP1 expression was significantly associated with six immune cells (B cells, CD4+ T cells, CD8+ T cells, macrophages, neutrophils, and dendritic cells) in most tumors, including colon adenocarcinoma (COAD), head and neck squamous cell carcinoma (HNSC), kidney renal clear cell carcinoma (KIRC), and liver hepatocellular carcinoma (LIHC) (P < 0.05). In particular, CD8+T cell infiltration, was also positively correlated with high PARP1 expression in bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), kidney renal papillary cell carcinoma (KIRP), brain lower grade glioma (LGG), LIHC, pancreatic adenocarcinoma (PAAD), pheochromocytoma and paraganglioma (PCPG), prostate adenocarcinoma (PRAD), rectum adenocarcinoma (READ), testicular germ cell tumors (TGCT), thymoma (THYM), uterine corpus endometrial carcinoma (UCEC), uveal melanoma (UVM) (P < 0.05, no data shown), and PARP1 expression was significantly positively correlated with the transcription levels of some of the 47 immune checkpoint genes, such as CD274, CTLA4, and PDCD1 in several tumors, including PAAD, LIHC, KIRC, HNSC, and BLCA (P < 0.05). A significant positive association between PARP1 expression and the number of immune neoantigen was found within COAD, KIRC, lung adenocarcinoma (LUAD), PAAD and THYM (P < 0.05), and there were also significantly positive correlations between PARP1 expression and TMB in many tumors like adrenocortical carcinoma (ACC), COAD, kidney chromophobe (KICH), LGG, LUAD, READ, skin cutaneous melanoma (SKCM) and stomach adenocarcinoma (STAD) (P < 0.05). In addition, high PARP1 expression was positively associated with microsatellite instability event in COAD, KIRP, BRCA, glioblastoma multiforme (GBM), lung squamous cell carcinoma (LUSC), LGG, READ, UCEC, SKCM and LUAD (P < 0.05).ConclusionsOur results highlight the significance of PARP1 alterations as pan-cancer predictive biomarkers for ICI treatment, and its expression levels seem to be correlated with the status of immunotherapy-associated signatures, thus may be a promising biomarker for predicting ICI response in several tumors.
Highlights
Novel immune checkpoint inhibitors (ICIs), including anticytotoxic T lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), and their ligands, PDL1 (CD274) and PD-L2 (CD273), have great potential for therapeutic efficacy in a variety of tumors, such as metastatic melanoma and non-small cell lung carcinoma (NSCLC), along with bladder urothelial cancer [1]
TIMER data showed high Poly (ADP-ribose) polymerases-1 (PARP1) expression was significantly associated with six immune cells (B cells, CD4+ T cells, CD8+ T cells, macrophages, neutrophils, and dendritic cells) in most tumors, including colon adenocarcinoma (COAD), head and neck squamous cell carcinoma (HNSC), kidney renal clear cell carcinoma (KIRC), and liver hepatocellular carcinoma (LIHC) (Figure 6)
We found that PARP1 expression was closely linked to microsatellite instability event, which suggested that high PARP1 expression was positively associated with microsatellite instability event in COAD, kidney renal papillary cell carcinoma (KIRP), breast invasive carcinoma (BRCA), glioblastoma multiforme (GBM), lung squamous cell carcinoma (LUSC), lower grade glioma (LGG), rectum adenocarcinoma (READ), uterine corpus endometrial carcinoma (UCEC), skin cutaneous melanoma (SKCM) and lung adenocarcinoma (LUAD), while a negative association was observed in pancreatic adenocarcinoma (PAAD) (Figure 10B)
Summary
Novel immune checkpoint inhibitors (ICIs), including anticytotoxic T lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), and their ligands, PDL1 (CD274) and PD-L2 (CD273), have great potential for therapeutic efficacy in a variety of tumors, such as metastatic melanoma and non-small cell lung carcinoma (NSCLC), along with bladder urothelial cancer [1]. In preclinical experiments on breast cancer cell lines, small-molecule PARP1/PD-L1 inhibitor conjugates demonstrated more significant apoptosis and cytotoxic efficacy compared to their separate agents [11]. These results suggest that could PARP1 alteration incorporate ICI treatment and seem to potentially predict ICI therapeutic values. A comprehensive analysis of the predictive values of PARP1 alteration for immune checkpoint inhibitor (ICI) effectiveness in tumors remains unclear, and the associations between its expression and immunotherapy signatures needs to be explored further
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