作者
James T. Neal,Xingnan Li,Junjie Zhu,Valeria Giangarrá,Caitlin L. Grzeskowiak,Jihang Ju,Iris H. Liu,Shin Heng Chiou,Ameen A. Salahudeen,Amber Rae Smith,Brian C. Deutsch,Lillian Liao,Allison Zemek,Fan Zhao,Kasper Karlsson,Liora Schultz,Thomas J. Metzner,Lincoln Nadauld,Yuen Yi Tseng,Sahar Alkhairy,Coyin Oh,Paula Keskula,Daniel Mendoza-Villanueva,Francisco Vega,Pamela L. Kunz,Joseph C. Liao,John T. Leppert,John B. Sunwoo,Chiara Sabatti,Jesse S. Boehm,William C. Hahn,Grace Zheng,Mark M. Davis,Calvin J. Kuo
摘要
In vitro cancer cultures, including three-dimensional organoids, typically contain exclusively neoplastic epithelium but require artificial reconstitution to recapitulate the tumor microenvironment (TME). The co-culture of primary tumor epithelia with endogenous, syngeneic tumor-infiltrating lymphocytes (TILs) as a cohesive unit has been particularly elusive. Here, an air-liquid interface (ALI) method propagated patient-derived organoids (PDOs) from >100 human biopsies or mouse tumors in syngeneic immunocompetent hosts as tumor epithelia with native embedded immune cells (T, B, NK, macrophages). Robust droplet-based, single-cell simultaneous determination of gene expression and immune repertoire indicated that PDO TILs accurately preserved the original tumor T cell receptor (TCR) spectrum. Crucially, human and murine PDOs successfully modeled immune checkpoint blockade (ICB) with anti-PD-1- and/or anti-PD-L1 expanding and activating tumor antigen-specific TILs and eliciting tumor cytotoxicity. Organoid-based propagation of primary tumor epithelium en bloc with endogenous immune stroma should enable immuno-oncology investigations within the TME and facilitate personalized immunotherapy testing.