FRI294 The Dopamine Agonist Cabergoline Targets Multiple Pathways To Inhibit PRL Secretion And Increases Stromal Fibrosis Via The Serotonin Receptor 5HTR1F
Authors: Zhang Dongyun , Hugo Willy , Bergsneider Marvin , Wang Marilene B , Kim Won , Vinters Harry V , Heaney Anthony P 
Published: October 2023

Disclosure: D. Zhang: None. W. Hugo: None. M. Bergsneider: None. M.B. Wang: None. W. Kim: None. H.V. Vinters: None. A.P. Heaney: None.

Prolactinomas (PRLomas) are comparatively common and make up ∼50% of all pituitary adenomas. Occurring in both genders, they can cause galactorrhea, amenorrhea and sub-fertility in females, and loss of libido and sexual dysfunction in males. Dopamine agonist (DA) therapy is an effective first line medical treatment in most PRLomas, and ∼1/3 of patients can stop therapy after 2 years and thereafter maintain normal prolactin (PRL) levels. However, 1/3 of patients require long-term DA therapy to maintain normal PRL levels and a further 1/3 of patients are either refractory to DA therapy or intolerant of their side effects including severe depression and/or anxiety. To begin to unravel potential mechanism(s) of on- and off-target effects of DA therapy, we used single cell RNA sequencing (scRNA-seq) to compare cellular composition and the transcriptional landscape in 3 surgically resected but previously cabergoline (CBG) treated and 3 surgically resected but dopamine agonist treatment naive PRLomas. We identified 6 major cell populations that included tumor (90.2%), immune (4.6%), stromal (4.3%), progenitor cells (0.5%), proliferating cells (0.25%), and erythrocytes (0.1%). In the tumor cell population, genes involved in hormone secretion regulation, such as SCG2, VGF, TIMP1, NNAT, and CALD1 were reduced in CBG-treated samples, consistent with the inhibitory effects of CBG on PRL hormone processing and secretion. Interestingly, we also observed a reduction in MHC-I complex HLA-A and B2M expression concomitant with an increase of CD8+ T cells in the CBG-treated PRL-oma samples. This group of cytotoxic CD8+ T cells expressed killing granule components, such as perforin (PRF1) and granzymes GZMA/H/K/M as well as the inflammatory cytokines CCL4/5. Further analysis to elucidate the upstream regulators of this pathway highlighted activation of IL2, and involvement of the inflammatory transcription factors NFκB and STATs in response to CBG treatment. We also noted previously unreported increased PRLoma expression of several genes implicated in psychological disorders such as PTN, PCLO, THSD7A, and TXNIP. Additionally, and confirming prior reports, we noted a higher stromal cell population in CBG-treated compared to non CBG-treated samples, with high fibroblast expression of the serotonin receptor HTR1F, potentially implicating HTR1F as a mediator of CBG-induced stromal fibrosis. In summary, our scRNAseq studies revealed key differences in the transcriptomic features of CBG-treated and -untreated prolactinomas, and suggest previously unknown activation of CD8+ T cells may play a role in the tumoricidal actions of CBG therapy. Furthermore, our observed induction of several genes implicated in psychological disorders may provide insight into the not infrequent side effects of mood alteration following DA therapy.

Presentation: Friday, June 16, 2023