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CD28 co-stimulatory domain enhances efficacy of CER T cell therapy compared to 4-1BB in an ovarian cancer mouse model

ABSTRACT: Ovarian cancer remains a significant cause of cancer-related mortality, with epithelial ovarian cancer (EOC) being the most common subtype. Despite advances in treatment, the 5-year survival rate for late-stage EOC remains low due to factors such as tumor heterogeneity and an immunosuppressive tumor microenvironment (TME). This study investigates the therapeutic potential of chimeric endocrine receptor (CER) T cells engineered to express follicle stimulating hormone (FSH) in a syngeneic mouse model of EOC expressing follicle stimulating hormone receptor (ID8-FSHR). We compared two different co-stimulatory domains—CD28ζ and 4-1BBζ—in FSH-CER T cells and found that FSH-CD28ζ CER T cells exhibited enhanced cytotoxicity, proliferation, and cytokine secretion in vitro and in vivo. In the ID8-FSHR mouse model, FSH-28ζ CER T cells significantly reduced tumor burden and extended survival compared to FSH-hBBζ and control CER T cells. However, the therapeutic efficacy was compromised by T cell exhaustion, with all FSH-CER T cells expressing high levels of exhaustion markers after 7 days. In summary, incorporating a CD28ζ costimulatory domain enhances the efficacy of FSH-CER T cells, highlighting their therapeutic potential in ovarian cancer and supporting the development of strategies to mitigate immune exhaustion.

ORGANISM(S): Mus musculus

PROVIDER: GSE303863 | GEO | 2026/05/14

REPOSITORIES: GEO

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CD28 co-stimulatory domain enhances efficacy of CER T cell therapy compared to 4-1BB in an ovarian cancer mouse model

Project description:Ovarian cancer remains a significant cause of cancer-related mortality, with epithelial ovarian cancer (EOC) being the most common subtype. Despite advances in treatment, the 5-year survival rate for late-stage EOC remains low due to factors such as tumor heterogeneity and an immunosuppressive tumor microenvironment (TME). This study investigates the therapeutic potential of chimeric endocrine receptor (CER) T cells engineered to express follicle stimulating hormone (FSH) in a syngeneic mouse model of EOC expressing follicle stimulating hormone receptor (ID8-FSHR). We compared two different co-stimulatory domains—CD28ζ and 4-1BBζ—in FSH-CER T cells and found that FSH-CD28ζ CER T cells exhibited enhanced cytotoxicity, proliferation, and cytokine secretion in vitro and in vivo. In the ID8-FSHR mouse model, FSH-28ζ CER T cells significantly reduced tumor burden and extended survival compared to FSH-hBBζ and control CER T cells. However, the therapeutic efficacy was compromised by T cell exhaustion, with all FSH-CER T cells expressing high levels of exhaustion markers after 7 days. In summary, incorporating a CD28ζ costimulatory domain enhances the efficacy of FSH-CER T cells, highlighting their therapeutic potential in ovarian cancer and supporting the development of strategies to mitigate immune exhaustion.

2026-04-27 | PXD066774 | Pride

Modeling FSHR function with hPSCs

Project description:Follicle-stimulating hormone (FSH) is crucial in the development and regulation of reproductive functions. We expressed MAC-tagged FSH receptor (FSHR) in HEK293 cells followed by affinity purification mass spectrometry analyses, to investigate interactome of FSHR at resting state and upon FSH stimulation. In total, 19 specific high-confidence interactors for WT FSHR and 14 for A189V FSHR, several of which have been linked to infertility.

2021-12-17 | MSV000088577 | MassIVE

Human pluripotent stem cell-derived cells endogenously expressing follicle-stimulating hormone receptors: modeling the function of an inactivating receptor mutation

Project description:Follicle-stimulating hormone (FSH) is crucial in the development and regulation of reproductive functions. The actions of human FSH and its receptor (FSHR) and mutations therein have mainly been studied using in vivo models, primary cells, cancer cells and cell lines ectopically expressing the FSHR. To allow studies of endogenous FSHR function in vitro, we differentiated FSHR-expressing cells from human pluripotent stem cells. FSH stimulation of the wild-type (WT), but not the inactivating Finnish founder mutant (A189V) receptor, activated the canonical cAMP-dependent signaling pathway and downstream mediators. Interestingly, the WT and A189V mutant receptors activated distinct pathways in a G-protein-coupled receptor signaling assay. FSH stimulation of WT FSHR-expressing cells induced phosphorylation of PI3Kp85a/g, MAPKAPK2 and proteins involved in calcium-dependent signaling, among others, while in the A189V mutant cells FSH induced phosphorylation of e.g., P90RSK, ERK3, and focal adhesion kinase. Lastly, we expressed FSHR in HEK293 cells followed by affinity purification mass spectrometry analyses, to investigate protein-protein interaction partners of FSHR at resting state and upon FSH stimulation. We found 19 specific high-confidence interacting proteins for WT FSHR and 14 for A189V FSHR, several of which have been linked to infertility. In conclusion, our protocol allows detailed studies of FSH action and disease modeling in human cells endogenously expressing FSHR.

2022-05-01 | GSE184352 | GEO

Functional and transcriptomic dose-response analysis of follicle-stimulating hormone in ex vivo mouse folliculogenesis and oogenesis

Project description:The gonadotropin-dependent phase of ovarian folliculogenesis primarily requires follicle-stimulating hormone (FSH) to support one or multiple early antral follicles, dependent on the species, to mature fully and support steroidogenesis, oogenesis, and ovulation, which critically sustain female reproductive cycles and fertility. At molecular levels, FSH binds to its membrane receptor, FSHR, in granulosa cells to activate a suite of genes and signal transduction pathways. Both insufficient FSH caused by genetic or non-genetic reasons and excessive FSH used for ovarian stimulation in assisted reproductive technology (ART) can cause poor female reproductive outcomes, but the underlying mechanisms remain elusive. Here, we used an ex vivo folliculogenesis and oogenesis system along with single-follicle and -oocyte RNA sequencing analysis and other approaches to investigate the effects of different concentrations of FSH on key follicular events. The results revealed that a minimum FSH threshold is required for follicle maturation, and such threshold is moderately variable among individual follicles. FSH at the subthreshold, threshold, and suprathreshold levels induced distinct expression patterns of follicle maturation-related genes and the entire follicular transcriptomics. The RNA-seq analysis identified several new genes and signaling pathways that may critically regulate follicle maturation. The treatment of excessive FSH resulted in multiple ovarian disorders including premature luteinization, high production of androgen and proinflammatory factors, and reduced expression of energy metabolism-related genes in oocytes. Together, our study enables a better understanding of the gonadotropin-dependent folliculogenesis, and the novel findings shed crucial insights into how ovarian stimulation with high doses of FSH used in ART impact follicular health, oocyte quality, pregnancy success, and systemic health.

2024-06-05 | GSE249196 | GEO

Caulerpin alleviates cyclophosphamide -induced ovarian dysfunction by modulating macrophage-associated granulosa cells senescence in breast cancer

Project description:In this study, xenograft tumors of the breast cancer cell line MDA-MB-231 in female BALB/c nude mice model were established. It demonstrates that cyclophosphamide (CTX) alone caused a remarkable ovarian damage, including irregular estrous cycles, follicle loss and reduced expression in anti-Mullerian hormone (AMH) and follicle-stimulating hormone receptor (FSHR), while the ovarian toxicity can be largely reduced after caulerpin treatment in mice and in vitro.

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Gene expression in cultured bovine ovarian granulosa

Project description:The growth of the mammalian ovarian follicle requires the formation of a fluid filled antrum, and maturation and differentiation of the ovarian granulosa cells, largely under the control of Follicle Stimulating Hormone (FSH). Many follicles will regress and die by a process called atresia at this early antral stage. We therefore decided to analyse the gene expression profiles of granulosa cells cultured in the presence or absence of FSH and Tumour Necrosis Factor-alpha (TNF-alpha), an apoptotic factor, to simulate the key influences. Different concentratons of FSH and TNFa in granulosa culture were used to determine effective conditions via estradiol and progesterone production, and cell number. RNA for the array experiments and quantitative real time PCR was extracted from cells cultured with FSH added at 0.33 and TNF-alpha at 50 ng/ml. Four treatments of : (1) FSH alone, (2) TNF-alpha alone, (3) FSH + TNF-alpha and (4) control = neither drug, with replicates (n=4, except controls n=3 ) were used to generate RNA for the gene expression arrays (n=15)

2014-05-20 | E-GEOD-42535 | biostudies-arrayexpress

Gene expression in cultured bovine ovarian granulosa

Project description:The growth of the mammalian ovarian follicle requires the formation of a fluid filled antrum, and maturation and differentiation of the ovarian granulosa cells, largely under the control of Follicle Stimulating Hormone (FSH). Many follicles will regress and die by a process called atresia at this early antral stage. We therefore decided to analyse the gene expression profiles of granulosa cells cultured in the presence or absence of FSH and Tumour Necrosis Factor-alpha (TNFα), an apoptotic factor, to simulate the key influences. Different concentratons of FSH and TNFa in granulosa culture were used to determine effective conditions via estradiol and progesterone production, and cell number. RNA for the array experiments and quantitative real time PCR was extracted from cells cultured with FSH added at 0.33 and TNFα at 50 ng/ml.

2014-05-20 | GSE42535 | GEO

Genome-wide analysis of gonadotropin-dependent gene expression and crosstalk of the regulatory pathways in the female ovaries

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Genome-wide analysis of gonadotropin-dependent gene expression and crosstalk of the regulatory pathways in the female ovaries

2016-02-03 | E-GEOD-77479 | biostudies-arrayexpress

Skeletal muscle-derived myostatin is a major endocrine driver of follicle-stimulating hormone synthesis

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2025-01-17 | GSE275041 | GEO

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