The effect of semaglutide on the progression of murine breast cancer

[I. A. Stanisavljević]

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Semaglutid, agonista receptora za glukagonu-sličan peptid 1, predstavlja antidijabetik koji pokazuje obećavajuća imunomodulatorna i antitumorska svojstva. Karcinom dojke predstavlja najčešći oblik maligniteta kod žena širom sveta. Cilj ovog istraživanja bio je da se ispita uticaj semaglutida na rast i progresiju tumora, kao i na antitumorski imunski odgovor u 4T1 mišjem modelu karcinoma dojke. Nakon indukcije tumora, BALB/C miševi su intraperitonealno tretirani semaglutidom. Primena semaglutida odložila je pojavu palpabilnog tumora i usporila rast primarnog tumora, kao i smanjila pojavu udaljenih metastaza u plućima i jetri. Lek nije ispoljio direktno citotoksičko dejstvo na ćelijske linije mišjeg i humanog karcinoma dojke in vitro, niti je značajno uticao na neoangiogenezu u tumorskom tkivu. Takođe, deplecija NK ćelija nije uticala na rast tumora kod miševa tretiranih semaglutidom, što ukazuje na mehanizam nezavisan od NK ćelija. Aplikacija semaglutida povećala je zastupljenost i sazrevanje CD11c⁺ dendritskih ćelija u slezini i tumorskom tkivu, istovremeno smanjujući zastupljenost CD4⁺CD25⁺FoxP3⁺ regulatornih T limfocita i njihovu produkciju IL-10. Dodatno, semaglutid je povećao zastupljenost i citotoksičku aktivnost CD8⁺ T limfocita, što se ogleda u smanjenoj ekspresiji PD-1 i produkciji IL-10, a povećanju ekspresije CD69, NKG2D, CD107a i granzima B. Deplecijom CD8⁺ T limfocita neutralisan je antitumorski efekat semaglutida, čime se potvrđuje da su ove ćelije ključna meta dejstva semaglutida. Rezultati ukazuju da semaglutid podstiče stečeni antitumorski imunski odgovor i predstavlja potencijalno efikasan dodatni imunoterapijski agens u lečenju karcinoma dojke.

Semaglutide, a glucagon-like peptide-1 receptor agonist, is an antidiabetic that has demonstrated promising immunomodulatory and antitumor properties. Breast cancer is the most common form of malignancy among women worldwide. The aim of this study was to investigate the effects of semaglutide on tumor growth and progression, as well as on the antitumor immune response in the 4T1 murine model of breast cancer. Following tumor induction, BALB/C mice were treated intraperitoneally with semaglutide. Semaglutide administration delayed the onset of palpable tumors and slowed the growth of primary tumors, while reducing the occurrence of distant metastases in the lungs and liver. The drug did not exhibit direct cytotoxic effects on murine or human breast cancer cell lines in vitro, nor did it significantly affect neovascularization in tumor tissue. Furthermore, NK cell depletion did not influence tumor growth in semaglutide-treated mice, indicating an NK cellindependent mechanism of action. Semaglutide treatment increased the presence and maturation of CD11c⁺ dendritic cells in the spleen and tumor tissue, while simultaneously reducing the percentage of CD4⁺CD25⁺FoxP3⁺ regulatory T cells and their production of IL10. Additionally, semaglutide enhanced both the presence and cytotoxic activity of CD8⁺ T cells, reflected in reduced expression of PD-1 and IL-10 production, alongside increased expression of CD69, NKG2D, CD107a, and granzyme B. Depletion of CD8⁺ T cells neutralized the antitumor effect of semaglutide, confirming that CD8⁺ T cells are the key target of semaglutide’s action. These results suggest that semaglutide promotes an adaptive antitumor immune response and represents a potentially effective adjunct immunotherapeutic agent in breast cancer treatment.

Semaglutid, karcinom dojke, antitumorski imunski odgovor, CD8+ T limfociti.

Semaglutide, breast cancer, antitumor immunity, CD8+ T cells.

618.19-006.6-08-097(043.3)

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