Organoid Modeling of the Tumor Immune Microenvironment

• Published in: Cell Vol. 175; no. 7; pp. 1972 - 1988.e16
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.12.2018
• Subjects: Animals; B7-H1 Antigen - immunology; biopsy; cancer; checkpoint inhibitor; coculture; Coculture Techniques; cytotoxicity; epithelium; Female; hosts; Humans; Immunotherapy; liquid-air interface; macrophages; Male; Mice; Mice, Inbred BALB C; Models, Immunological; Neoplasm Proteins - immunology; neoplasms; Neoplasms, Experimental - immunology; Neoplasms, Experimental - pathology; Neoplasms, Experimental - therapy; organoid; Organoids - immunology; Organoids - pathology; PD-1; PDO; receptors; Receptors, Antigen, T-Cell - immunology; single-cell RNA-seq; T cell receptor; T-lymphocytes; TCR; Tumor Microenvironment - immunology; tumor-infiltrating lymphocyte; TCR; T cell receptor; immunotherapy; tumor-infiltrating lymphocyte; single-cell RNA-seq; PDO; cancer; PD-1; checkpoint inhibitor; organoid
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2018.11.021

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.