TY - JOUR
KW - Animals
KW - B7-H1 Antigen
KW - Coculture Techniques
KW - Female
KW - Humans
KW - Immunotherapy
KW - Male
KW - Mice
KW - Mice, Inbred BALB C
KW - Models, Immunological
KW - Neoplasm Proteins
KW - Neoplasms, Experimental
KW - organoids
KW - PD-1
KW - PDO
KW - Receptors, Antigen, T-Cell
KW - T cell receptor
KW - TCR
KW - Tumor Microenvironment
KW - Cancer
KW - checkpoint inhibitor
KW - Immunotherapy
KW - organoid
KW - single-cell RNA-seq
KW - tumor-infiltrating lymphocyte
AU - James T. Neal
AU - Xingnan Li
AU - Junjie Zhu
AU - Valeria Giangarra
AU - Caitlin L. Grzeskowiak
AU - Jihang Ju
AU - Iris H. Liu
AU - Shin-Heng Chiou
AU - Ameen A. Salahudeen
AU - Amber R. Smith
AU - Brian C. Deutsch
AU - Lillian Liao
AU - Allison J. Zemek
AU - Fan Zhao
AU - Kasper Karlsson
AU - Liora M. Schultz
AU - Thomas J. Metzner
AU - Lincoln D. Nadauld
AU - Yuen-Yi Tseng
AU - Sahar Alkhairy
AU - Coyin Oh
AU - Paula Keskula
AU - Daniel Mendoza-Villanueva
AU - Francisco M. De La Vega
AU - Pamela L. Kunz
AU - Joseph C. Liao
AU - John T. Leppert
AU - John B. Sunwoo
AU - Chiara Sabatti
AU - Jesse S. Boehm
AU - William C. Hahn
AU - Grace X. Y. Zheng
AU - Mark M. Davis
AU - Calvin J. Kuo
AB - 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.
BT - Cell
DA - 2018-12-13
DO - 10.1016/j.cell.2018.11.021
IS - 7
LA - eng
N2 - 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.
PY - 2018
SP - 1972
EP - 1988.e16
T2 - Cell
TI - Organoid Modeling of the Tumor Immune Microenvironment
VL - 175
SN - 1097-4172
ER -