Journal
CELL
Volume 175, Issue 7, Pages 1972-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2018.11.021
Keywords
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Categories
Funding
- Stanford Dean's Fellowship
- Stanford Cancer Institute Fellowship
- American Cancer Society Postdoctoral Fellowship [124574-PF-13-296-01-TBG]
- Stanford Discovery Innovation Fund
- NSF [DMS 1712800]
- St. Baldrick's Fellowship
- NHLBI [T32 IT32HL098049]
- Ovarian Cancer Research Alliance
- NCI Cancer Target Discovery and Development Network [CA176299, CA176058]
- NIDDK Intestinal Stem Cell Consortium [U01DK085527]
- NIAID Novel, Alternative Model Systems for Enteric Diseases [U19AI116484]
- NCI Ras Synthetic Lethal Network [U01CA199241, U01DE025188]
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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 PDOTILs 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.
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