SNAI1-dependent upregulation of CD73 increases extracellular adenosine release to mediate immune suppression in TNBC

Abstract

Triple-negative subtype of breast cancer (TNBC) is hallmarked by frequent disease relapse and shows highest mortality rate. Although PD-1/PD-L1 immune checkpoint blockades have recently shown promising clinical benefits, the overall response rate remains largely insufficient. Hence, alternative therapeutic approaches are warranted. Given the immunosuppressive properties of CD73-mediated adenosine release, CD73 blocking approaches are emerging as attractive strategies in cancer immunotherapy. Understanding the precise mechanism regulating the expression of CD73 is required to develop effective anti-CD73-based therapy. Our previous observations demonstrate that the transcription factors driving epithelial-to-mesenchymal transition (EMT-TF) can regulate the expression of several inhibitory immune checkpoints. Here we analyzed the role of the EMT-TF SNAI1 in the regulation of CD73 in TNBC cells. We found that doxycycline-driven SNAI1 expression in the epithelial -like TNBC cell line MDA-MB-468 results in CD73 upregulation by direct binding to the CD73 proximal promoter. SNAI1-dependent upregulation of CD73 leads to increased production and release of extracellular adenosine by TNBC cells and contributes to the enhancement of TNBC immunosuppressive properties. Our data are validated in TNBC samples by showing a positive correlation between the mRNA expression of CD73 and SNAI1. Overall, our results reveal a new CD73 regulation mechanism in TNBC that participates in TNBC-mediated immunosuppression and paves the way for developing new treatment opportunities for CD73-positive TNBC.

IGJ suppresses breast cancer growth and metastasis by inhibiting EMT via the NF‑κB signaling pathway

“…In addition to the previously described classical pathways, certain growth factors, including epidermal growth factor, insulin growth factor, hepatocyte growth factor, fibroblast growth factor and platelet-derived growth factor have also been found to trigger the EMT program ( 33 - 35 ). Moreover, it has been indicated that hypoxia-inducible factor 1α, inflammatory signals (NF-κB) and cytokines (IL-1β), and TNFα also induce the occurrence of EMT ( 36 ). Such pathways and cytokines act together in the occurrence of EMT in tumors.…”

Breaking Barriers: The Promise and Challenges of Immune Checkpoint Inhibitors in Triple-Negative Breast Cancer

“…Cancer cells can induce a phenotypic shift in macrophages, promoting the polarization of tumor-associated macrophages (TAMs) toward an M2-like immunosuppressive phenotype. This shift is orchestrated by metabolites, such as lactate and adenosine, which are abundantly produced in the glycolytic TME of TNBC [36,38]. Adenosine is a purine nucleoside that can suppress T cell function by binding to specific adenosine receptors (A2A and A2B) on the surface of T cells.…”

Immune Checkpoint Blockade Therapy for Breast Cancer: Lessons from Epithelial–Mesenchymal Transition

“…We and others have demonstrated that the EMT program can regulate the expression of CD73. CD73 is robustly expressed on more-mesenchymal murine and human breast cancer cell lines relative to those displaying more-epithelial features [ 77 , 79 , 88 , 89 ]. Direct induction of the EMT program by transforming growth factor beta (TGFβ), TWIST1, or SNAI1 resulted in elevated expression of CD73 in more-epithelial human breast cancer cells [ 77 , 88 , 89 ].…”

“…CD73 is robustly expressed on more-mesenchymal murine and human breast cancer cell lines relative to those displaying more-epithelial features [ 77 , 79 , 88 , 89 ]. Direct induction of the EMT program by transforming growth factor beta (TGFβ), TWIST1, or SNAI1 resulted in elevated expression of CD73 in more-epithelial human breast cancer cells [ 77 , 88 , 89 ]. Moreover, SNAI1 binding was also observed within the CD73 promoter in both human as well as murine cancer cells that had activated the EMT program [ 77 , 79 ].…”