In Vivo Multi-Dimensional CRISPR Screens Identify Lgals2 as an Immunotherapy Target in Triple-Negative Breast Cancer [CRISPR]

Immune checkpoint inhibitors exhibit limited response rates in patients with triple-negative breast cancer, suggesting that additional immune escape mechanisms may exist. Here, we performed two-step customized in vivo CRISPR screens targeting disease-related immune genes using different mouse models with multi-dimensional immune deficiency characteristics. We identified Lgals2 as a candidate regulator in TNBC involving immune escape. Mechanistic studies demonstrated that tumor cell-intrinsic Lgals2 induced the increased number of tumor-associated macrophages, as well as the M2-like polarization and proliferation of macrophages through CSF1/CSF1R axis, which resulted in the immunosuppressive nature of the TNBC microenvironment. Collectively, our results provide a theoretical basis for LGALS2 as a potential immunotherapy target in TNBC. Overall design: In vivo CRISPR screenings were performed to assess immune-response features of disease-related immune genes under different immune pressures.