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CD95/Fas protects triple negative breast cancer from anti-tumor activity of NK cells

ABSTRACT: Summary The apoptosis inducing receptor CD95/Fas has multiple tumorigenic activities. In different genetically engineered mouse models tumor-expressed CD95 was shown to be critical for cell growth. Using a combination of immune-deficient and immune-competent mouse models, we now establish that loss of CD95 in metastatic triple negative breast cancer (TNBC) cells prevents tumor growth by modulating the immune landscape. CD95-deficient, but not wild-type, tumors barely grow in an immune-competent environment and show an increase in immune infiltrates into the tumor. This growth reduction is caused by infiltrating NK cells and does not involve T cells or macrophages. In contrast, in immune compromised mice CD95 k.o. cells are not growth inhibited, but they fail to form metastases. In summary, we demonstrate that in addition to its tumor and metastasis promoting activities, CD95 expression by tumor cells can exert immune suppressive activities on NK cells, providing a new target for immune therapy. Graphical abstract Highlights • CD95 expression promotes primary TNBC growth in immune-competent mice• CD95 KO TNBC cells do not metastasize in immune-deficient mice• Loss of CD95 triggers a pro-inflammatory program affecting the immune landscape• Loss of CD95 causes tumor destruction by NK cells in immune-competent mice Immunology; Cell biology; Cancer

SUBMITTER: Qadir A

PROVIDER: S-EPMC8593563 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundBreast cancer is the most prevalent female tumor, of which triple-negative breast cancer (TNBC) accounts for about 15%. Characterized by its aggressive nature and limited treatment options, TNBC currently stands as a significant clinical challenge. This study aimed to investigate the effects of icariin (ICA) on TNBC and explore the underlying molecular mechanism.MethodsCell viability was assessed using CCK-8 assay, whereas the impact of ICA on cell proliferation was determined using colony formation assay and detection of proliferating cell nuclear antigen protein. Wound healing and transwell assays were used to evaluate the effects of ICA on cell migration and invasion, respectively. Flow cytometry was used to analyze cell cycle distribution and apoptosis. Transmission electron microscopy and monodansylcaverine staining were performed to detect the induction of autophagy, whereas molecular docking was conducted to predict the potential targets associated with autophagy. The in vivo anti-tumor effects of ICA were evaluated using a TNBC 4T1 xenograft mouse model. Protein expression levels were examined using immunoblotting and immunohistochemistry.ResultsIn vitro, ICA effectively suppressed the viability, proliferation, migration, and invasion of TNBC cells and induced G0/G1 phase cell cycle arrest, apoptosis, and autophagy in TNBC cells by regulating the adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/Unc-51-like kinase 1 (ULK1) signaling pathway. The knockdown of AMPK and inhibition of autophagy with 3-methyladenine reversed the effects of ICA, highlighting the importance of AMPK and autophagy in the anti-cancer mechanism of ICA. In vivo, ICA significantly inhibited TNBC growth, promoted autophagy, and regulated AMPK/mTOR/ULK1 pathway.ConclusionsOur findings demonstrated that ICA exerts anti-cancer effects against TNBC and the associated molecular mechanisms. This study will help to facilitate further preclinical and clinical investigations for the treatment of TNBC.

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CD95/Fas protects triple negative breast cancer from anti-tumor activity of NK cells

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