Androgen receptor affects the response to immune checkpoint therapy by suppressing PD-L1 in hepatocellular carcinoma

Jiang, Guangyi; Shi, Liang; Zheng, Xue-Yong; Zhang, Xinjie; Wu, Ke; Liu, Boqiang; Yan, Peijian; Liang, Xiao; Yu, Tunan; Wang, Yifan; Cai, Xiujun

doi:10.18632/aging.103231

Cited by 32 publications

(23 citation statements)

References 44 publications

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“…Similar to Jiang et al (2020), we identified a direct interaction between AR and the CD274 gene body using CUT&Tag. However, since we were able to profile AR binding sites genome-wide, we also identified an AR binding signal at the NFKBIA promoter.…”

Section: Discussionmentioning

confidence: 88%

“…To our knowledge, this is the first study identifying a relationship between AR activity and PD-L1 expression in thyroid cancer. Recently, Jiang et al (2020) characterized AR suppression of PD-L1 in hepatocellular carcinoma. In combination, these findings point to a previously unappreciated role AR has on PD-L1 expression in multiple tissue types and, given that the PD-1/PD-L1 axis is an actionable immunotherapeutic target for various cancers, indicate that AR activity can impact the response to immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

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Androgen Activity Is Associated With PD-L1 Downregulation in Thyroid Cancer

O’Connell

Dadafarin

Jones

et al. 2021

Front. Cell Dev. Biol.

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Thyroid cancer is the most prevalent endocrine malignancy in the United States with greater than 53,000 new cases in 2020. There is a significant gender disparity in disease incidence as well, with women developing thyroid cancer three times more often than men; however, the underlying cause of this disparity is poorly understood. Using RNA-sequencing, we profiled the immune landscape of papillary thyroid cancer (PTC) and identified a significant inverse correlation between androgen receptor (AR) levels and the immune checkpoint molecule PD-L1. The expression of PD-L1 was then measured in an androgen responsive-thyroid cancer cell line. Dihydrotestosterone (DHT) treatment resulted in significant reduction in surface PD-L1 expression in a time and dose-dependent manner. To determine if androgen-mediated PD-L1 downregulation was AR-dependent, we treated cells with flutamide, a selective AR antagonist, and prior to DHT treatment to pharmacologically inhibit AR-induced signaling. This resulted in a > 90% restoration of cell surface PD-L1 expression, suggesting a potential role for AR activity in PD-L1 regulation. Investigation into the AR binding sites showed AR activation impacts NF-kB signaling by increasing IkBα and by possibly preventing NF-kB translocation into the nucleus, reducing PD-L1 promoter activation. This study provides evidence of sex-hormone mediated regulation of immune checkpoint molecules in vitro with potential ramification for immunotherapies.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Androgen Activity Is Associated With PD-L1 Downregulation in Thyroid Cancer

O’Connell

Dadafarin

Jones

et al. 2021

Front. Cell Dev. Biol.

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“…Patients with advanced HCC are at substantial risk of death, and chemotherapy remains unsatisfied with a survival benefit. Evidence has proved the potential of immune checkpoint inhibitors (ICIs) in HCC treatment [ 8 , 35 – 37 ]. However, only a small portion of HCC patients achieved a therapeutic effect from ICIs.…”

Section: Discussionmentioning

confidence: 99%

Identification of a prognostic and therapeutic immune signature associated with hepatocellular carcinoma

Peng

Liu

et al. 2021

Cancer Cell Int

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Background Hepatocellular carcinoma (HCC) is one of the most prevalent and inflammation-associated cancers. The tumor microenvironment (TME) plays an essential role in HCC development and metastasis, leading to poor prognosis. The overall TME immune cells infiltration characterizations mediated by immune-related genes (IRGs) remain unclear. In this study, we aimed to investigate whether immune-related genes could be indicators for the prognosis of HCC patients and TME cell infiltration characterization as well as responses to immunotherapy. Methods We obtained differentially expressed immune-related genes (DE IRGs) between normal liver tissues and liver cancer tissues from The Cancer Genome Atlas (TCGA) database. To identify the prognostic genes and establish an immune risk signature, we performed univariable Cox regression survival analysis and the Least Absolute Shrinkage and Selector Operation (LASSO) regression based on the DE IRGs by robust rank aggregation method. Cox regression analysis was used to identify independent prognostic factors in HCC. We estimated the immune cell infiltration in TME via CIBERSORT and immunotherapy response through TIDE algorithm. Results We constructed an immune signature and validated its predictive capability. The immune signature included 7 differentially expressed IRGs: BIRC5, CACYBP, NR0B1, RAET1E, S100A8, SPINK5, and SPP1. The univariate and multivariate cox analysis showed that the 7-IRGs signature was a robust independent prognostic factor in the overall survival of HCC patients. The 7-IRG signature was associated with some clinical features, including gender, vascular invasion, histological grade, clinical stage, T stage. We also found that the 7-IRG signature could reflect the infiltration characterization of different immunocytes in the tumor microenvironment (TME) and had a good correlation with immune checkpoint molecules, revealing that the poor prognosis might be partly due to immunosuppressive TME. The Tumour Immune Dysfunction and Exclusion (TIDE) analysis data showed that the 7-IRG signature had great potential for indicating the immunotherapy response in HCC patients. The mutation analysis demonstrated a significant difference in the tumor mutation burden (TMB) between the high- and low-risk groups, partially explaining this signature's predictive value. Conclusion In a word, we constructed and validated a novel, immune-related prognostic signature for HCC patients. This signature could effectively indicate HCC patients' survival and immunotherapy response. And it might act as potential immunotherapeutic targets for HCC patients.

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“…Preclinical evidence has suggested a potential therapeutic synergy by combining AR modulation and PD-1 blockade. Androgens are immunosuppressive and target both innate and adaptive immune systems to dampen the immune response [28][29][30][31][32][33][34]. Inhibition of AR sensitizes cancer cells to immunemediated killing.…”

Section: Investigator's Assessmentmentioning

confidence: 99%

“…Inhibition of AR sensitizes cancer cells to immunemediated killing. AR suppresses PD-L1 expression by binding to the PD-L1 promotor and directly attenuating PD-L1 gene transcription [29,30]. In addition, AR signaling inhibits thymocyte production [31], whereas AR blockade has been shown to increase naive T cell generation resulting in a larger diversity of T cell repertoire that could potentially respond to PD-1 blockade [32,33].…”

Section: Investigator's Assessmentmentioning

confidence: 99%

A Phase II Clinical Trial of Pembrolizumab and Enobosarm in Patients with Androgen Receptor-Positive Metastatic Triple-Negative Breast Cancer

et al. 2020

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Lessons Learned The combination of enobosarm and pembrolizumab was well tolerated and showed a modest clinical benefit rate of 25% at 16 weeks. Future trials investigating androgen receptor‐targeted therapy in combination with immune checkpoint inhibitors are warranted. Background Luminal androgen receptor is a distinct molecular subtype of triple‐negative breast cancer (TNBC) defined by overexpression of androgen receptor (AR). AR‐targeted therapy has shown modest activity in AR‐positive (AR+) TNBC. Enobosarm (GTx‐024) is a nonsteroidal selective androgen receptor modulator (SARM) that demonstrates preclinical and clinical activity in AR+ breast cancer. The current study was designed to explore the safety and efficacy of the combination of enobosarm and pembrolizumab in patients with AR+ metastatic TNBC (mTNBC). Methods This study was an open‐label phase II study for AR+ (≥10%, 1+ by immunohistochemistry [IHC]) mTNBC. Eligible patients received pembrolizumab 200 mg intravenous (IV) every 3 weeks and enobosarm 18 mg oral daily. The primary objective was to evaluate the safety of enobosarm plus pembrolizumab and determine the response rate. Peripheral blood, tumor biopsies, and stool samples were collected for correlative analysis. Results The trial was stopped early because of the withdrawal of GTx‐024 drug supply. Eighteen patients were enrolled, and 16 were evaluable for responses. Median age was 64 (range 36–81) years. The combination was well tolerated, with only a few grade 3 adverse events: one dry skin, one diarrhea, and one musculoskeletal ache. The responses were 1 of 16 (6%) complete response (CR), 1 of 16 (6%) partial response (PR), 2 of 16 (13%) stable disease (SD), and 12 of 16 (75%) progressive disease (PD). Response rate (RR) was 2 of 16 (13%). Clinical benefit rate (CBR) at 16 weeks was 4 of 16 (25%). Median follow‐up was 24.9 months (95% confidence interval [CI], 17.5–30.9). Progression‐free survival (PFS) was 2.6 months (95% CI, 1.9–3.1) and overall survival (OS) was 25.5 months (95% CI, 10.4–not reached [NR]). Conclusion The combination of enobosarm and pembrolizumab was well tolerated, with a modest clinical benefit rate of 25% at 16 weeks in heavily pretreated AR+ TNBC without preselected programmed death ligand‐1 (PD‐L1). Future clinical trials combining AR‐targeted therapy with immune checkpoint inhibitor (ICI) for AR+ TNBC warrant investigation.

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Androgen receptor affects the response to immune checkpoint therapy by suppressing PD-L1 in hepatocellular carcinoma

Cited by 32 publications

References 44 publications

Androgen Activity Is Associated With PD-L1 Downregulation in Thyroid Cancer

Androgen Activity Is Associated With PD-L1 Downregulation in Thyroid Cancer

Identification of a prognostic and therapeutic immune signature associated with hepatocellular carcinoma

A Phase II Clinical Trial of Pembrolizumab and Enobosarm in Patients with Androgen Receptor-Positive Metastatic Triple-Negative Breast Cancer

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