Organoid Modeling of the Tumor Immune Microenvironment

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • B7-H1 Antigen / immunology
  • Coculture Techniques
  • Female
  • Humans
  • Immunotherapy
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Models, Immunological*
  • Neoplasm Proteins / immunology
  • Neoplasms, Experimental / immunology*
  • Neoplasms, Experimental / pathology
  • Neoplasms, Experimental / therapy
  • Organoids / immunology*
  • Organoids / pathology
  • Receptors, Antigen, T-Cell / immunology*
  • Tumor Microenvironment / immunology*

Substances

  • B7-H1 Antigen
  • CD274 protein, human
  • Neoplasm Proteins
  • Receptors, Antigen, T-Cell