Upregulation of CXCL1 and LY9 contributes to BRCAness in ovarian cancer and mediates response to PARPi and immune checkpoint blockade

Chen, Tingting; Yu, Tong; Zhuang, Shuping; Geng, Yiding; Xue, Junwen; Wang, Jiayi; Ai, Liqiang; Chen, Bin; Zhao, Zhangxiang; Li, Yawei; Wang, Jinghao; Liang, Haihai; Xu, Yan; Gu, Yunyan

doi:10.1038/s41416-022-01836-0

Cited by 6 publications

(5 citation statements)

References 31 publications

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“…Very few approaches have associated gene expression with HRD status [18,19,65]. Whereas a sixty-gene signature [18] and a two-gene signature ( CXCL1 , LY9 ) [19] have focused on microarray data, a recent approach using RNA sequencing data identified a 249-gene signature to predict HRD [65]. We observed a number of overlaps with our 24-gene BRCA signature and a high concordance of signature scores in our training (TCGA) and validation (MUI) cohorts, indicating the reliability of our approach.…”

Section: Discussionmentioning

confidence: 99%

“…Genomic scars are predictive but do not allow direct functional interpretation, whereas gene expression signatures could be an alternative in this regard. Very few approaches have associated gene expression with HRD status [18,19,65]. Whereas a sixty-gene signature [18] and a two-gene signature ( CXCL1 , LY9 ) [19] have focused on microarray data, a recent approach using RNA sequencing data identified a 249-gene signature to predict HRD [65].…”

Section: Discussionmentioning

confidence: 99%

“…However, further efforts are undertaken to identify various biomarkers based on different modalities, such as gene expression or methylation, in the context of different cancer types [17][18][19][20][21]. Deleterious BRCA1 mutations and/or PARP inhibition can trigger an immune response at least in part through the cGAS-STING pathway [20][21][22][23][24], suggesting advantages for combined immunotherapies.…”

Section: Introductionmentioning

confidence: 99%

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Integrated immunogenomic analyses of high-grade serous ovarian cancer reveal vulnerability to combination immunotherapy

Gronauer,

Madersbacher,

Monfort-Lanzas

et al. 2024

Preprint

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Background: High-grade serous ovarian cancer (HGSOC) remains the most lethal gynecologic malignancy despite new therapeutic concepts, including poly-ADP-ribose polymerase inhibitors (PARPis) and antiangiogenic therapy. The efficacy of immunotherapies is modest, but clinical trials investigating the potential of combination immunotherapy with PARPis are underway. Homologous recombination repair deficiency (HRD) or BRCAness and the composition of the tumor microenvironment appear to play a critical role in determining the therapeutic response. Methods: We conducted comprehensive immunogenomic analyses of HGSOC using data from several patient cohorts, including a new cohort from the Medical University of Innsbruck (MUI). Machine learning methods were used to develop a classification model for BRCAness from gene expression data. Integrated analysis of bulk and single-cell RNA sequencing data was used to delineate the tumor immune microenvironment and was validated by immunohistochemistry. The impact of PARPi and BRCA1 mutations on the activation of immune-related pathways was studied in vitro using ovarian cancer cell lines, RNA sequencing, and immunofluorescence analysis. Results: We identified a predictive 24-gene signature to determine BRCAness. Comprehensive analysis of the tumor microenvironment allowed us to identify patient samples with BRCAness and high immune infiltration. Further characterization of these samples revealed increased infiltration of immunosuppressive cells, including tumor-associated macrophages (TAMs) expressing TREM2, C1QA, and LILRB4, as identified by further analysis of single-cell RNA sequencing data and gene expression analysis of samples from patients receiving combination therapy with PARPi and anti-PD-1. PARPi activated the cGAS-STING signaling pathway and the downstream innate immune response in a similar manner to HGSOC patients with BRCAness status. We have developed a web application (https://ovrseq.icbi.at) and an associated R package OvRSeq, which allow for comprehensive characterization of ovarian cancer patient samples and assessment of a vulnerability score that enables stratification of patients to predict response to the mentioned combination immunotherapy. Conclusions: Genomic instability in HGSOC affects the tumor immune environment, and TAMs play a crucial role in modulating the immune response. Based on various datasets, we have developed a diagnostic application that uses RNA sequencing data not only to comprehensively characterize HGSOC but also to predict vulnerability and response to combination immunotherapy. Keywords: High-grade serous ovarian cancer, BRCAness, PARP inhibitor, immunotherapy, vulnerability, RNA sequencing, tumor-associated macrophages, tumor immune microenvironment

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Integrated immunogenomic analyses of high-grade serous ovarian cancer reveal vulnerability to combination immunotherapy

Gronauer,

Madersbacher,

Monfort-Lanzas

et al. 2024

Preprint

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show abstract

“…found that upregulation of CXCL1 with downregulation of SV2A and upregulation of SLAMF3 with downregulation of CHRNB3 can be constructed as a two-gene pair signature for BRCAness in ovarian cancer that predicts improved OS, PFS, and increased multi-omics alterations in homologous recombination genes. Furthermore, these could predict enhanced sensitivity to immune checkpoint blockade and poly ADP ribose polymerase (PARP) inhibitors, confirming SLAMF3 as an attractive immunotherapeutic target in ovarian cancer ( 61 ).…”

Section: Slamf Receptors In Solid Tumorsmentioning

confidence: 94%

Signaling lymphocytic activation molecule family receptors as potential immune therapeutic targets in solid tumors

Gunes,

Rosen,

Shachar

et al. 2024

Front. Immunol.

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Recently, cancer immunotherapy has revolutionized cancer treatment. Various forms of immunotherapy have a manageable safety profile and result in prolongation of overall survival in patients with solid tumors, but only in a proportion of patients. Various factors in the tumor microenvironment play critical roles and may be responsible for this lack of therapeutic response. Signaling lymphocytic activation molecule family (SLAMF) members are increasingly being studied as factors impacting the tumor immune microenvironment. SLAMF members consist of nine receptors mainly expressed in immune cells. However, SLAMF receptors have also been detected in cancer cells, and they may be involved in a spectrum of anti-tumor immune responses. Here, we review the current knowledge of the expression of SLAMF receptors in solid tumors and tumor-infiltrating immune cells and their association with patient outcomes. Furthermore, we discuss the therapeutic potential of targeting SLAMF receptors to improve outcomes of cancer therapy in solid tumors. We believe the research on SLAMF receptor-targeted strategies may enhance anti-cancer immunity in patients with solid tumors and improve clinical outcomes.

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“…Here, we predicted the LAYNrelated protein-protein interaction networks with GeneMANIA database online tools (http://genemania.org). As a result, the top 20 LAYN-related genes were enriched and shown from the GeneMANIA database (Figure 2B), among these, SV2A [15], BIK [16] and CLEC4M [17] were reported play an important role in oncogenesis in ovarian cancer. Interestingly, we also identi ed some immune-related genes that interacted with LAYN such as GPR37 [18] and MRGPRX2 [19], enlightening us to consider the potential mechanism of LAYN during the cancer-associated immune process.…”

Section: The Protein-protein Interaction Network Illustrated the Pote...mentioning

confidence: 99%

LAYN acts as a prognostic biomarker in ovarian cancer by engaging T cell exclusion and dysfunction

Song

2022

Preprint

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Background Ovarian cancer (OV) is one of the commonest gynecological cancer, especially in the developed world. Layilin (LAYN) is associated with multiple types of cancer. However, it remains unclear about LAYN’s underlying roles and potential mechanisms in ovarian cancer. Methods The expression status of LAYN and clinic information of patients in OV were investigated using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Results High expression of LAYN forecasted a shorter survival time in all OV datasets we used, indicating high LAYN expression was significantly associated with poor prognosis in OV patients. Bioinformatic analyses showed that LAYN expression level was an independent factor associated with OV prognosis. We also proved the significant association of LAYN expression level with T cell exclusion and resistance to immune checkpoint blockade (ICB). Further analyses revealed that LAYN may play its role on tumor immunity through the TGF-beta signaling pathway. Conclusions This is the first study to reveal the molecular functions of LAYN in OV. Our study suggests that overexpressed LAYN might boost T cell exclusion and ICB resistance by activating TGF-beta signaling pathway, resulting in a poor prognosis for OV patients. This study shed a light on understanding potential prognostic biomarkers and therapeutic targets in OV.

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Upregulation of CXCL1 and LY9 contributes to BRCAness in ovarian cancer and mediates response to PARPi and immune checkpoint blockade

Cited by 6 publications

References 31 publications

Integrated immunogenomic analyses of high-grade serous ovarian cancer reveal vulnerability to combination immunotherapy

Integrated immunogenomic analyses of high-grade serous ovarian cancer reveal vulnerability to combination immunotherapy

Signaling lymphocytic activation molecule family receptors as potential immune therapeutic targets in solid tumors

LAYN acts as a prognostic biomarker in ovarian cancer by engaging T cell exclusion and dysfunction

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