Role of PARP Inhibitors in Cancer Immunotherapy: Potential Friends to Immune Activating Molecules and Foes to Immune Checkpoints

Franzese, Ornella; Graziani, Grazia

doi:10.3390/cancers14225633

Cited by 11 publications

(10 citation statements)

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“…9 O). Similarly, studies have demonstrated that PARPIs [ 55 , 56 ] and cetuximab [ 57 ] can further improve the prognosis of immunotherapy refractory or ineligible patients. Finally, we assessed the expression levels of HER-2 in TIDE subtypes to offer insights into HER-2-targeted therapy.…”

Section: Resultsmentioning

confidence: 99%

Tumor immune dysfunction and exclusion subtypes in bladder cancer and pan-cancer: a novel molecular subtyping strategy and immunotherapeutic prediction model

Zheng,

Hai,

Chen

et al. 2024

J Transl Med

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Background Molecular subtyping is expected to enable precise treatment. However, reliable subtyping strategies for clinical application remains defective and controversial. Given the significance of tumor immune dysfunction and exclusion (TIDE), we aimed to develop a novel TIDE-based subtyping strategy to guide personalized immunotherapy in the bladder cancer (BC). Methods Transcriptome data of BC was used to evaluate the heterogeneity and the status of TIDE patterns. Subsequently, consensus clustering was applied to classify BC patients based on TIDE marker-genes. Patients’ clinicopathological, molecular features and signaling pathways of the different TIDE subtypes were well characterized. We also utilize the deconvolution algorithms to analyze the tumor microenvironment, and further explore the sensitivity and mechanisms of each subtype to immunotherapy. Furthermore, BC patient clinical information, real-world BC samples and urine samples were collected for the validation of our findings, which were used for RNA-seq analysis, H&E staining, immunohistochemistry and immunofluorescence staining, and enzyme-linked immunosorbent assay. Finally, we also explored the conservation of our novel TIDE subtypes in pan-cancers. Results We identified 69 TIDE biomarker genes and classified BC samples into three subtypes using consensus clustering. Subtype I showed the lowest TIDE status and malignancy with the best prognosis and highest sensitivity to immune checkpoint blockade (ICB) treatment, which was enriched of metabolic related signaling pathways. Subtype III represented the highest TIDE status and malignancy with the poorest prognosis and resistance to ICB treatment, resulting from its inhibitory immune microenvironment and T cell terminal exhaustion. Subtype II was in a transitional state with intermediate TIDE level, malignancy, and prognosis. We further confirmed the existence and characteristics of our novel TIDE subtypes using real-world BC samples and collected patient clinical data. This subtyping method was proved to be more efficient than previous known methods in identifying non-responders to immunotherapy. We also propose that combining our TIDE subtypes with known biomarkers can potentially improve the sensitivity and specificity of these biomarkers. Moreover, besides guiding ICB treatment, this classification approach can assist in selecting the frontline or recommended drugs. Finally, we confirmed that the TIDE subtypes are conserved across the pan-tumors. Conclusions Our novel TIDE-based subtyping method can serve as a powerful clinical tool for BC and pan-cancer patients, and potentially guiding personalized therapy decisions for selecting potential beneficiaries and excluding resistant patients of ICB therapy.

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Section: Resultsmentioning

confidence: 99%

Tumor immune dysfunction and exclusion subtypes in bladder cancer and pan-cancer: a novel molecular subtyping strategy and immunotherapeutic prediction model

Zheng,

Hai,

Chen

et al. 2024

J Transl Med

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“…PAPR inhibitors can result in SL and promote the death of tumor cells [57]. And PARP inhibitors can increase CD4 + T cells, CD8 + T cells, Dendritic cell(DC), NK cells in ltration and the expression of PD-L1 in the TME via the cGAS-STING pathway [14][15][16]. Study also found that Loss of POLQ can suppress the growth of Esophageal Squamous Cell Carcinoma and promote the instability of genome through the cGAS-STING pathway [18].Therefore, inhibition of POLQ may associate with the function of PARP inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…This process is involved in the Homologous recombination (HR) pathway and is signi cantly observed in breast, ovarian, and pancreatic cancers [12,13]. HR as an important repair pathway of DSB repair, can impact the Tumor immune microenvironment (TIME) and the immune response, thus inhibiting the occurrence of tumor [14,15]. HR can increase the in ltration of immune cells when encountering the DNA damage, which could change the TIME [16].…”

Section: Introductionmentioning

confidence: 99%

“…POLQ plays a role in TIME and loss of POLQ will contribute to the potential activation of the innate immune response, which can be through the cyclic GMP-AMP synthase (cGAS) and STING pathway [18]. And inhibiting POLQ combined with PARP inhibitors can enhance anti-tumor immune response and stimulate the produce of CD8 + T cells, natural killer (NK) cells and the release of pro-in ammatory cytokines through the cGAS-STING pathway [14,19]. POLQ is unregulated in tumor and the overexpression of POLQ is correlated with Homologous-recombination-de cient (HRD) status and a poor clinical outcome [8,20].…”

Section: Introductionmentioning

confidence: 99%

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A Comprehensive Multiomics Analysis Identified POLQ as a Promising Prognostic Biomarker in Pan-Cancer

Yang

Huang

et al. 2023

Preprint

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Background DNA polymerase (POLQ) is a unique A-family polymerase that is correlated with homologous recombination and plays a vital role in maintaining the stability of the genome. Tumor immune microenvironment (TIME) plays an important role in the occurrence and development of tumor. POLQ is associated with TIME and a poor prognosis. However, the roles of POLQ in human cancers are still unclear. Hence, studying POLQ maybe provide a new strategy for tumor-immune therapy. Methods The mRNA expression data and clinical information of cancer were downloaded from TCGA and GTEx. We explored the prognosis, mutation, copy number variation (CNV) and single nucleotide variations (SNV), microsatellite instability (MSI), tumor mutational burden (TMB), mismatch repair (MMR) gene mutation levels and DNA methyltransferase expression, immune infiltration, enrichment analysis and pathway, and drug sensitivity analysis via Kaplan-Meier curves, cBioPortal, GSCA, TCGA, TIMER, The LinkedOmics database and Multiomics Data. Results POLQ expression was associated with adverse outcomes in uterine corpus endometrial carcinoma (UCEC), kidney renal papillary cell carcinoma (KIRP) and liver hepatocellular carcinoma (LIHC) patients. Additionally, our study revealed that genomic alteration of POLQ was associated with tumorigenesis in multiple tumors and POLQ was correlated with MSI, TMB, MMR gene mutation and DNA methyltransferase expression. POLQ expression was positively correlated with the infiltration of immune cells including B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells, especially in kidney renal clear cell carcinoma (KIRC), thyroid carcinoma (THCA). And POLQ expression was positively correlated with the immune score and immune checkpoint in KIRC and THCA. In particular, POLQ can increase the resistance to drug, especially to PAPR inhibitors. Conclusion POLQ could be a novel biomarker and a potential target for immune-related therapy in pan-cancer.

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“…Ovarian carcinomas in germline BRCA-mutated women have a more elevated mutational burden and a higher number of neoantigens that stimulate the recruitment of tumor-infiltrating lymphocytes (TILs) [ 55 , 56 , 57 ]. These tumors revealed increased numbers of CD3+ and CD8+ TILs and elevated expression of PD-1 and PD-L1 and may therefore represent a subset of malignancies particularly sensitive to treatment with immune checkpoint inhibitors alone or in combination with PARP inhibitors and/or chemotherapy [ 58 ].…”

Section: Hrd In Ovarian Cancermentioning

confidence: 99%

Homologous Recombination Deficiency in Ovarian Cancer: from the Biological Rationale to Current Diagnostic Approaches

Mangogna

Munari

Pepe

et al. 2023

JPM

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The inability to efficiently repair DNA double-strand breaks using the homologous recombination repair pathway is defined as homologous recombination deficiency (HRD). This molecular phenotype represents a positive predictive biomarker for the clinical use of poly (adenosine diphosphate [ADP]-ribose) polymerase inhibitors and platinum-based chemotherapy in ovarian cancers. However, HRD is a complex genomic signature, and different methods of analysis have been developed to introduce HRD testing in the clinical setting. This review describes the technical aspects and challenges related to HRD testing in ovarian cancer and outlines the potential pitfalls and challenges that can be encountered in HRD diagnostics.

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Role of PARP Inhibitors in Cancer Immunotherapy: Potential Friends to Immune Activating Molecules and Foes to Immune Checkpoints

Cited by 11 publications

References 325 publications

Tumor immune dysfunction and exclusion subtypes in bladder cancer and pan-cancer: a novel molecular subtyping strategy and immunotherapeutic prediction model

Tumor immune dysfunction and exclusion subtypes in bladder cancer and pan-cancer: a novel molecular subtyping strategy and immunotherapeutic prediction model

A Comprehensive Multiomics Analysis Identified POLQ as a Promising Prognostic Biomarker in Pan-Cancer

Homologous Recombination Deficiency in Ovarian Cancer: from the Biological Rationale to Current Diagnostic Approaches

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