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HER2∆16 Engages ENPP1 To Promote an Immune Cold Microenvironment in Breast Cancer.

The tumor immune microenvironment (TIME) is a critical determinant of therapeutic response. However, the mechanisms regulating its modulation are not fully understood. HER216, an oncogenic splice variant of the human epidermal growth factor receptor (HER2), has been implicated in breast cancer and other tumor types as a driver of tumorigenesis and metastasis. Nevertheless, the underlying mechanisms of HER2Δ16-mediated oncogenicity remain poorly understood. Here, we show that HER2∆16 expression is not exclusive to the clinically HER2+ subtype and associates with a poor clinical outcome in breast cancer. To understand how HER2 variants modulated the tumor microenvironment, we generated transgenic mouse models expressing either proto-oncogenic HER2 or HER2∆16 in the mammary epithelium. We found that HER2∆16 tumors were immune cold, characterized by low immune infiltrate and an altered cytokine profile. Using an epithelial cell surface proteomic approach, we identified ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) as a functional regulator of the immune cold microenvironment. We generated a knock-in model of HER2Δ16 under the endogenous promoter to understand the role of Enpp1 in aggressive HER2+ breast cancer. Knockdown of Enpp1 in HER2Δ16-derived tumor cells resulted in decreased tumor growth, which correlated with increased T-cell infiltration. These findings suggest that HER2Δ16-dependent Enpp1 activation associates with aggressive HER2+ breast cancer through its immune modulatory function. Our study provides a better understanding of the mechanisms underlying HER2Δ16-mediated oncogenicity and highlights ENPP1 as a potential therapeutic target in aggressive HER2+ breast cancer.

Date de publication
13 juin 2023
Attalla SS, Boucher J, Proud H, Taifour T, Zuo D, Sanguin-Gendreau V, Ling C, Johnson G, Li V, Luo RB, Kuasne H, Papavasiliou V, Walsh LA, Barok M, Joensuu H, Park M, Roux PP, Muller WJ
Référence PubMed
Cancer Immunol Res 2023
ID PubMed
McGill University, Montreal, QC, Canada.