HER2Δ16 Engages ENPP1 to Promote an Immune-Cold Microenvironment in Breast Cancer

Abstract

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.

From mechanism to therapy: the journey of CD24 in cancer

“…Various small molecule inhibitors targeting ENPP1 have shown efficacy in preclinical models, suggesting potential for clinical applications. These inhibitors not only counteract the immunosuppressive effects of ENPP1 but also may enhance the effects of other immunotherapeutic strategies by enabling a more robust immune response against tumors (121)(122)(123).…”