Wu Bogang, Thant Win, Bitman Elena, Liu Ting, Liu Jie, Paschalis Eleftherios I, Xu Katherine H, Nieman Linda T, Ting David T, Thimmiah Nayana, Sun Sheng, Abelman Rachel O, Isakoff Steven J, Spring Laura M, Bardia Aditya, Ellisen Leif W
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, 02114, USA.
bioRxiv. 2024 Dec 5:2024.12.02.626446. doi: 10.1101/2024.12.02.626446.
Immune exclusion inhibits anti-tumor immunity and response to immunotherapy, but its mechanisms remain poorly defined. Here, we demonstrate that Trophoblast Cell-Surface Antigen 2 (TROP2), a key target of emerging anti-cancer Antibody Drug Conjugates (ADCs), controls barrier-mediated immune exclusion in Triple-Negative Breast Cancer (TNBC) through Claudin 7 association and tight junction regulation. TROP2 expression is inversely correlated with T cell infiltration and strongly associated with outcomes in TNBC. Loss-of-function and reconstitution experiments demonstrate TROP2 is sufficient to drive tumor progression in vivo in a CD8 T cell-dependent manner, while its loss deregulates expression and localization of multiple tight junction proteins, enabling T cell infiltration. Employing a humanized TROP2 syngeneic TNBC model, we show that TROP2 targeting via hRS7, the antibody component of Sacituzumab govitecan (SG), enhances the anti-PD1 response associated with improved T cell accessibility and effector function. Correspondingly, TROP2 expression is highly associated with lack of response to anti-PD1 therapy in human breast cancer. Thus, TROP2 controls an immune exclusion program that can be targeted to enhance immunotherapy response.
免疫排斥抑制抗肿瘤免疫和对免疫疗法的反应，但其机制仍不清楚。在此，我们证明滋养层细胞表面抗原2（TROP2）是新兴的抗癌抗体药物偶联物（ADC）的关键靶点，它通过与Claudin 7结合和紧密连接调节来控制三阴性乳腺癌（TNBC）中屏障介导的免疫排斥。TROP2表达与T细胞浸润呈负相关，且与TNBC的预后密切相关。功能丧失和重建实验表明，TROP2足以以CD8 T细胞依赖的方式在体内驱动肿瘤进展，而其缺失会使多种紧密连接蛋白的表达和定位失调，从而使T细胞浸润。利用人源化TROP2同基因TNBC模型，我们发现通过hRS7（戈沙妥珠单抗（SG）的抗体成分）靶向TROP2可增强与改善T细胞可及性和效应功能相关的抗PD1反应。相应地，TROP2表达与人类乳腺癌对抗PD1治疗的反应缺乏高度相关。因此，TROP2控制着一种免疫排斥程序，可通过靶向该程序来增强免疫治疗反应。
