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

• DOI: 10.1158/2326-6066.cir-22-0140
• Publication Date: 2023-06-13T17:57:01Z
• Authors: Sherif Samer Attalla; Jonathan Boucher; Hailey Proud; Tarek Taifour; Dongmei Zuo; Virginie Sanguin-...; Chen Ling; Gabriella Johnson; Vincent Li; Robin B. Luo; Hellen Kuasne; Vasilios Papavasi...; Logan A. Walsh; Mark Barok; Heikki Joensuu; Morag Park; Philippe P. Roux; William J. Muller
• Keywords: Tumor progression; Tumor initiation

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