Organoid Modeling of the Tumor Immune Microenvironment

Abstract

SUMMARY In vitro cancer cultures, including 3-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 immunooncology investigations within the TME and facilitate personalized immunotherapy testing.

Stable expansion of high‐grade serous ovarian cancer organoids requires a low‐Wnt environment

“…It is possible that including other cell types in the organoid model, such as stromal and immune cells, could further advance its capacity to generate data which are predictive of clinical responses in patients (Neal et al , ).…”

“…ª 2020 The Authors The EMBO Journal 39: e104013 | 2020 therapy, which is of critical importance for the development of new treatment approaches, paired organoid cultures could be generated from primary disease and after recurrence in the same patients. It is possible that including other cell types in the organoid model, such as stromal and immune cells, could further advance its capacity to generate data which are predictive of clinical responses in patients (Neal et al, 2018).…”

Xenograft and organoid model systems in cancer research

“…They demonstrated that the T‐cell receptors are highly conserved between the PDTO culture and the parental tumour. Crucially, they showed that the PDTO cultures functionally recapitulate the PD‐1/PD‐L1‐dependent immune checkpoint (Neal et al , ).…”

Mouse models of uveal melanoma: Strengths, weaknesses, and future directions

“…3D cultures derived from patient tumor specimens can be grafted into mice (patient-derived organoid xenografts) and faithfully match the molecular phenotypes and even treatment responses of the source tumors (Sachs et al, 2018;Vlachogiannis et al, 2018). Some even allow for the study of the tumor microenvironment, as they incorporate stromal cells such as cancer-associated fibroblasts and lymphocytes (Neal et al, 2018). In the uveal melanoma literature, there have been a few reports of 3D cultures in which cells form tumorspheres (Angi, Versluis, & Kalirai, 2015;Lapadula et al, 2019;Valyi-Nagy et al, 2018).…”