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

O’Connell, Timmy; Dadafarin, Sina; Jones, Melanie; Rodríguez, Tomás; Gupta, Anvita; Shin, Edward J.; Moscatello, Augustine; Iacob, Codrin; Islam, Humayun; Tiwari, Raj K.; Geliebter, Jan

doi:10.3389/fcell.2021.663130

Cited by 14 publications

(16 citation statements)

References 49 publications

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“…Thus, a combination of immune-modulatory agents with pro-senescence agents, apoptosis inducers, and SASP modulators should be considered when evaluating pro-senescence modalities as a tool for effective cancer management. Further, we have observed that AR activation decreases the expression of PDL-1 in 84E7 and K1-lentiAR cells, rendering cells more susceptible to immune destruction by T cells [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

“…We have previously described the generation of AR-transfected cell lines 84E7, K1-lentiAR, and 8505C-lentiAR [ 21 , 43 ]. Briefly, 84E7 cells were derived through the transfection of 8505C cells with pcDNA3.1 containing the androgen receptor, followed by selection and clonal isolation [ 21 ].…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, 84E7 cells were derived through the transfection of 8505C cells with pcDNA3.1 containing the androgen receptor, followed by selection and clonal isolation [ 21 ]. K1-lentiAR and 8505C-lentiAR were generated via transfection with lentiviral constructs containing the AR, followed by population selection [ 43 ].…”

Section: Methodsmentioning

confidence: 99%

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Androgen Receptor Activation Induces Senescence in Thyroid Cancer Cells

Gupta

Carnazza

Jones

et al. 2023

Cancers

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Thyroid cancer (TC) is the most common endocrine malignancy, with an approximately three-fold higher incidence in women. TCGA data indicate that androgen receptor (AR) RNA is significantly downregulated in PTC. In this study, AR-expressing 8505C (anaplastic TC) (84E7) and K1 (papillary TC) cells experienced an 80% decrease in proliferation over 6 days of exposure to physiological levels of 5α-dihydrotestosterone (DHT). In 84E7, continuous AR activation resulted in G1 growth arrest, accompanied by a flattened, vacuolized cell morphology, with enlargement of the cell and the nuclear area, which is indicative of senescence; this was substantiated by an increase in senescence-associated β-galactosidase activity, total RNA and protein content, and reactive oxygen species. Additionally, the expression of tumor suppressor proteins p16, p21, and p27 was significantly increased. A non-inflammatory senescence-associated secretory profile was induced, significantly decreasing inflammatory cytokines and chemokines such as IL-6, IL-8, TNF, RANTES, and MCP-1; this is consistent with the lower incidence of thyroid inflammation and cancer in men. Migration increased six-fold, which is consistent with the clinical observation of increased lymph node metastasis in men. Proteolytic invasion potential was not significantly altered, which is consistent with unchanged MMP/TIMP expression. Our studies provide evidence that the induction of senescence is a novel function of AR activation in thyroid cancer cells, and may underlie the protective role of AR activation in the decreased incidence of TC in men.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Androgen Receptor Activation Induces Senescence in Thyroid Cancer Cells

Gupta

Carnazza

Jones

et al. 2023

Cancers

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“…Determining ASF1B expression levels could be considered a high priority for predicting the efficacy of PD-L1 targeted therapy. Two recent studies show a role for androgens in PD-L1 expression (62) and cell proliferation (63). Both show evidence of a protective role for androgen signaling in thyroid cancer.…”

Section: Discussionmentioning

confidence: 95%

ASF1B: A Possible Prognostic Marker, Therapeutic Target, and Predictor of Immunotherapy in Male Thyroid Carcinoma

Qiu

Shi

et al. 2022

Front. Oncol.

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BackgroundThyroid carcinoma (TC) is the most common malignant endocrine tumor worldwide. Several studies have documented that male patients with TC have a higher rate of metastasis and disease recurrence than female patients. However, the mechanism underlying this observation is not completely clear. The goal of our research was to investigate the potential key candidate genes and pathways related to TC progression in male patients at the molecular level.MethodsA total of 320 samples were obtained from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. Hub genes were screened out using weighted gene coexpression network analysis (WGCNA) and a protein–protein interaction (PPI) network analysis. Survival analysis was used to identify hub genes associated with disease-free survival (DFS) rates. Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression (ESTIMATE) data were used to assess the relationship between hub genes and immune cell infiltration. The molecular mechanism and biological functions of hub genes were explored using RT-qPCR, Western blot, Cell Counting Kit-8 Assay, flow cytometry, Transwell assays, and scratch assays.ResultsForty-seven hub genes were identified, and the survival analysis demonstrated that anti-silencing function 1B (ASF1B) was the sole independent risk factor for poor DFS in male TC patients. Possible associations between the results from the ESTIMATE analysis showed that the ASF1B expression level was related to the ESTIMATE score, immune score, and T-cell regulatory (Treg) infiltration level. Through in vitro cell function experiments, we verified that knockdown of ASF1B inhibited KTC-1 cell proliferation, promoted cell apoptosis, and blocked cell cycle. The silencing of ASF1B reduced protein kinase B (AKT), phospho-AKT (p-AKT), and forkhead box p3 (FOXP3) in KTC-1 cells. Moreover, FOXP3 overexpression markedly restored the cell migration, invasion, and proliferation abilities repressed by ASF1B knockdown.ConclusionsOur results indicate that ASF1B can be considered a prognostic marker, therapeutic target, and predictor of immunotherapy response in male thyroid cancer patients. However, further in-depth studies are required to validate this finding.

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“…In many gender disparity tumors, such as HCC or thyroid, AR bind the PD-L1 promotor and so downregulates PD-L1 expression [ 22 , 23 ]. Guan et al [ 24 ] noted that blocking AR and PD-L1 correlated with a reduction in prostate tumor growth, which provides a connection between androgens and therapy resistance.…”

Section: Introductionmentioning

confidence: 99%

Role of Nivolumab in the Modulation of PD-1 and PD-L1 Expression in Papillary and Clear Cell Renal Carcinoma (RCC)

et al. 2022

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The expression and cellular mechanisms of programmed cell death-1 protein (PD-1) and its ligands (PD-L1 and PD-L2) in renal cancer cells are not well known. Here, we aimed to investigate the response of renal carcinoma subtypes to the immune checkpoint inhibitor nivolumab and its impact on related signaling pathways. All cell lines analyzed (clear cell (cc)RCC (Caki-1, RCC31) and papillary (p)RCC (ACHN, RCC30)) expressed PD-1 and both ccRCC cell lines, and RCC30 expressed PD-L1. Nivolumab treatment at increasing doses led to increased PD-1 levels in analyzed cells and resulted in aggressive behavior of pRCC but diminished this behavior in ccRCC. The analysis of PD-1/PD-L1-associated signaling pathways demonstrated increased AKT activity in Caki-1 and RCC30 cells but decreased activity in ACHN and RCC31 cells, while ribosomal protein S6 remained largely unchanged. Androgen receptors are related to RCC and were predominantly increased in RCC30 cells, which were the only cells that formed nivolumab-dependent spheroids. Finally, all cell lines exhibited a complex response to nivolumab treatment. Since the pRCC cells responded with increased tumorigenicity and PD-1/PD-L1 levels while ccRCC tumorigenicity was diminished, further studies are needed to improve nivolumab-based therapy for renal carcinoma subtypes, especially the identification of response-involved molecular pathways.

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

Cited by 14 publications

References 49 publications

Androgen Receptor Activation Induces Senescence in Thyroid Cancer Cells

Androgen Receptor Activation Induces Senescence in Thyroid Cancer Cells

ASF1B: A Possible Prognostic Marker, Therapeutic Target, and Predictor of Immunotherapy in Male Thyroid Carcinoma

Role of Nivolumab in the Modulation of PD-1 and PD-L1 Expression in Papillary and Clear Cell Renal Carcinoma (RCC)

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