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Cell. 2018 Dec 13;175(7):1972-1988.e16. doi: 10.1016/j.cell.2018.11.021.

Organoid Modeling of the Tumor Immune Microenvironment.

Author information

1
Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA.
2
Department of Electrical Engineering, Stanford University School of Engineering, Stanford, CA, USA.
3
10x Genomics, Pleasanton, CA, USA.
4
Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Stanford, CA, USA.
5
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
6
Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, CA, USA.
7
Department of Urology, Stanford University School of Medicine, Stanford, CA, USA.
8
Broad Institute of Harvard and MIT, Cambridge, MA, USA.
9
TOMA Biosciences, Foster City, CA, USA.
10
Department of Otolaryngology, Stanford University School of Medicine, Stanford, CA, USA.
11
Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA; Department of Statistics, Stanford University School of Humanities and Sciences, Stanford, CA, USA.
12
Broad Institute of Harvard and MIT, Cambridge, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
13
Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Stanford, CA, USA; Howard Hughes Medical Institute and Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA.
14
Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: cjkuo@stanford.edu.

Abstract

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.

KEYWORDS:

PD-1; PDO; T cell receptor; TCR; cancer; checkpoint inhibitor; immunotherapy; organoid; single-cell RNA-seq; tumor-infiltrating lymphocyte

PMID:
30550791
DOI:
10.1016/j.cell.2018.11.021

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