In vivo multidimensional CRISPR screens identify Lgals2 as an immunotherapy target in triple-negative breast cancer

Abstract

Immune checkpoint inhibitors exhibit limited response rates in patients with triple-negative breast cancer (TNBC), 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 multidimensional immune-deficiency characteristics. In vivo screens characterized gene functions in the different tumor microenvironments and recovered canonical immunotherapy targets such as Ido1 . In addition, functional screening and transcriptomic analysis 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 the CSF1/CSF1R axis, which resulted in the immunosuppressive nature of the TNBC microenvironment. Blockade of LGALS2 using an inhibitory antibody successfully arrested tumor growth and reversed the immune suppression. Collectively, our results provide a theoretical basis for LGALS2 as a potential immunotherapy target in TNBC.

Arene–Arene Coupled Disulfamethazines (or Sulfadiazine)-Phenanthroline-Metal(II) Complexes were Synthesized by In Situ Reactions and Inhibited the Growth and Development of Triple-Negative Breast Cancer through the Synergistic Effect of Antiangiogenesis, Anti-Inflammation, Pro-Apoptosis, and Cuproptosis

“…TNBC is a female cancer with a high recurrence rate, high malignancy rate, and low survival rate. , MDA-MB-231 cells were selected for subsequent experiments, as it is one of the commonly used cell lines for studying TNBC. It is expected to provide potential value for the research and development of metal-based complexes for the treatment of TNBC.…”

“…The absence of expression of ER, PR, and HER-2 results in a heterogeneous subtype of breast cancer called tripe-negative breast cancer (TNBC). TNBC has a high early recurrence rate, limited treatment options, and poor prognosis by comparing with other subtypes of breast cancer. , In clinical treatment, cis-dichlorodiammine platinum (DDP) has been widely used in different types of cancer, but it has serious side effects and drug resistance . At present, cisplatin shows the disadvantage of drug resistance in the treatment of TNBC .…”

Differential whole-genome doubling based signatures for improvement on clinical outcomes and drug response in patients with breast cancer

“…Among them, 21 genes have been recorded in the DisGeNET [ 38 ] database (v7.0), excluding C9orf68, and 8 risk genes (ANLN [ 39 ], BIRC3 [ 40 ], CD200R1 [ 41 ], CD226 [ 42 ], CLEC10A [ 43 ], PPP2R2B [ 44 ], PTPRC [ 45 ], SPN [ 46 ]) are already reported for BRCA. We also identified 8 other genes (CD79A [ 47 ], EOMES [ 48 ], CAMK4 [ 49 ], FGL2 [ 50 ], KLRB1 [ 51 ], LGALS2 [ 52 ], SLA2 [ 53 ], STAP1 [ 54 ] that have been reported in previous BRCA studies. In addition, three cancer genes (BIRC3, CD79A, and PTPRC) overlapped with the Cancer Gene Census in COSMIC (v97) [ 55 ], further supporting their relevance in the context of cancer, majorly BRCA.…”

Pan-cancer analysis of NUP155 and validation of its role in breast cancer cell proliferation, migration, and apoptosis

“…The expression of NUP155 mRNA in breast cancer cell lines was significantly higher than that in healthy breast cells. Triple-negative breast cancer (TNBC) has the worst prognosis and poses significant treatment challenges among breast cancer subtypes, with a 5-year survival rate of only 11% in advanced stages [ 39 ]. Two TNBC cell lines (MDA-MB-231 and BT-549 cells) were used in subsequent in vitro experiments.…”