复旦发现三阴性乳腺癌免疫新靶点

　　三阴性乳腺癌的雌激素受体、孕激素受体、人类表皮生长因子受体HER2均为阴性，对内分泌治疗和抗HER2靶向治疗无效。近年来，随着免疫细胞程序死亡受体PD-1及其配体PD-L1等免疫检查点抑制剂的问世，为癌症免疫治疗带来了希望。不过，免疫检查点抑制剂对三阴性乳腺癌患者的有效率不高，这表明患者体内还可能存在额外的免疫逃逸机制。

　　2022年6月29日，美国科学促进会《科学》旗下《科学进展》在线发表复旦大学附属肿瘤医院吉芃、龚悦、金明亮、吴怀亮、国琳玮、裴雨晨、柴文君、江一舟、刘引、马晓燕、狄根红、胡欣、邵志敏等学者的研究报告，发现了三阴性乳腺癌免疫治疗新靶点。

　　该研究利用体内基因编辑技术，通过两轮聚合酶链反应扩增，对具有多种免疫缺陷特征的不同小鼠模型进行疾病相关免疫基因筛选，分析了不同肿瘤微环境的基因功能特征，并恢复了吲哚胺双加氧酶IDO1等经典免疫治疗靶点。此外，功能筛选和转录组分析确定半乳糖凝集素LGALS2是涉及三阴性乳腺癌免疫逃逸的的候选调节因子之一。LGALS2可选择性结合T淋巴细胞的β半乳糖苷，从而诱发T淋巴细胞凋亡。对复旦大学附属肿瘤医院360例三阴性乳腺癌患者肿瘤标本分析发现，LGALS2显著高表达于肿瘤细胞，且肿瘤显著较大、分级显著较高。而且，LGALS2仅显著促进体内肿瘤生长，对体外肿瘤增殖影响不大。机制分析表明，肿瘤细胞内部LGALS2可诱导肿瘤相关巨噬细胞数量增加，并通过巨噬细胞集落刺激因子CSF1及其受体CSF1R促进巨噬细胞M2样极化和增殖，导致三阴性乳腺癌微环境免疫抑制性。利用LGALS2抗体可成功阻止三阴性乳腺癌肿瘤生长并且逆转免疫抑制。

体内疾病相关免疫基因基因编辑筛选确定候选肿瘤相关免疫基因

体内疾病相关免疫基因筛选揭示不同免疫压力下选定基因免疫反应特征

LGALS2可在体内而非在体外影响肿瘤生长

LGALS2可以引起肿瘤微环境免疫细胞浸润

单细胞RNA测序揭示LGALS2可诱发肿瘤微环境巨噬细胞极化

LGALS2通过集落刺激因子CSF1促进巨噬细胞M2样极化和增殖

阻断LGALS2可增强对三阴性乳腺癌的抗肿瘤免疫反应

LGALS2高表达于三阴性乳腺癌并与M2样巨噬细胞标志物相关

　　因此，该研究结果表明，LGALS2有望成为三阴性乳腺癌免疫治疗新靶点。

Sci Adv. 2022 Jun 29;8(26):eabl8247.

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

Ji P, Gong Y, Jin ML, Wu HL, Guo LW, Pei YC, Chai WJ, Jiang YZ, Liu Y, Ma XY, Di GH, Hu X, Shao ZM.

Fudan University Shanghai Cancer Center, Shanghai, China; Shanghai Medical College, Fudan University, Shanghai, China.

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.

PMID: 35767614

DOI: 10.1126/sciadv.abl8247