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Organoid Modeling of the Tumor Immune Microenvironment.

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.

SUBMITTER: Neal JT

PROVIDER: S-EPMC6656687 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Organoid Modeling of the Tumor Immune Microenvironment.

Neal James T JT Li Xingnan X Zhu Junjie J Giangarra Valeria V Grzeskowiak Caitlin L CL Ju Jihang J Liu Iris H IH Chiou Shin-Heng SH Salahudeen Ameen A AA Smith Amber R AR Deutsch Brian C BC Liao Lillian L Zemek Allison J AJ Zhao Fan F Karlsson Kasper K Schultz Liora M LM Metzner Thomas J TJ Nadauld Lincoln D LD Tseng Yuen-Yi YY Alkhairy Sahar S Oh Coyin C Keskula Paula P Mendoza-Villanueva Daniel D De La Vega Francisco M FM Kunz Pamela L PL Liao Joseph C JC Leppert John T JT Sunwoo John B JB Sabatti Chiara C Boehm Jesse S JS Hahn William C WC Zheng Grace X Y GXY Davis Mark M MM Kuo Calvin J CJ

Cell 20181201 7

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 syngene ...[more]

PMID: 30550791

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Project description:The interaction of neoplastic cells with their tumor microenvironment (TME) is required for cancer progression. However, in vitro cancer models, including recent in vitro 3-dimensional (3D) organoid cultures of primary human tumors, are typically comprised exclusively of neoplastic epithelium, with stromal and/or immune interactions requiring artificial reconstitution. As relevant to cancer immunotherapy, the unified co-culture of primary tumor epithelia with their endogenous, syngeneic tumor-infiltrating lymphocytes (TILs) as a cohesive unit has remained particularly elusive. Here, we used a single 3D air-liquid interface (ALI) methodology to successfully propagate 3D Patient-Derived Tumor Organoids (PDOs) as primary tumor epithelia together with native immune and myofibroblast stromal compartments without reconstitution. Derived from >100 diverse human surgically resected tumor samples or from murine tumors in syngeneic immunocompetent mice, PDOs preserved cancer histologic subtypes and mutational spectrum with endogenous T, B, NK cells and macrophages integrally embedded amidst the tumor epithelium. PDO-based TILs accurately recapitulated the T cell receptor (TCR) spectrum of the original tumors, as determined by a robust droplet-based immune profiling solution that links gene expression and immune repertoire in single cells. Anti-PD-1 or anti-PD-L1 treatment of organoids from murine tumors from syngeneic immunocompetent hosts induced activation and cytolytic activity of tumor antigen-specific TILs, indicating successful PDO modeling of immune checkpoint blockade (ICB) and anti-tumor immunity. Crucially, the anti-PD-1 antibody nivolumab activated TILs in PDOs from human lung, renal and melanoma clinical tumor resections. The organoid-based propagation of primary tumor epithelium en bloc with its endogenous immune stroma should facilitate mechanistic investigation of TME-specific local tumor immunity, with applications for functional testing of individualized patient immunotherapy responses.

Dataset Information

Organoid Modeling of the Tumor Immune Microenvironment.

Publications

Organoid Modeling of the Tumor Immune Microenvironment.

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