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Neal, James T.; Li, Xingnan; Zhu, Junjie; Giangarra, Valeria; Grzeskowiak, Caitlin L.; Ju, Jihang; Liu, Iris H.; Chiou, Shin-Heng; Salahudeen, Ameen A.; Smith, Amber R.; Deutsch, Brian C.; Liao, Lillian; Zemek, Allison J.; Zhao, Fan; Karlsson, Kasper; Schultz, Liora M.; Metzner, Thomas J.; Nadauld, Lincoln D.; Tseng, Yuen-Yi; Alkhairy, Sahar; Oh, Coyin; Keskula, Paula; Mendoza-Villanueva, Daniel; De La Vega, Francisco M.; Kunz, Pamela L.; Liao, Joseph C.; Leppert, John T.; Sunwoo, John B.; Sabatti, Chiara; Boehm, Jesse S.; Hahn, William C.; Zheng, Grace X.Y.; Davis, Mark M.; Kuo, Calvin J.
Cell, 12/2018, Volume: 175, Issue: 7Journal Article
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. Display omitted •Air-liquid interface (ALI) patient-derived tumor organoids (PDO) retain immune cells•5′ V(D)J and RNA-seq from the same single cells allows robust immune characterization•T cell receptor repertoire is highly conserved between tumor and PDO•ALI PDOs functionally recapitulate the PD-1/PD-L1-dependent immune checkpoint The tumor-immune microenvironment is modeled using a patient-derived organoid approach that preserves the original tumor T cell receptor spectrum and successfully models immune checkpoint blockade.
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