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Colorectal cancer organoids drive patient-specific inflammation, cytotoxicity and tissue-residency programs in NK cells

ABSTRACT: Natural killer (NK) cells represent a promising strategy for cellular cancer immunotherapy, but it remains unclear which patients benefit by such therapies. Using co-cultures of primary human allogenic NK cells and patient-derived colon cancer organoids (PDOs), we could stratify PDOs into NK cell “highly susceptible” and “rather resistant” groups reflected by differential expression of NKG2D-ligands, MHC class I and CEACAM. RNA-seq unveiled that hypoxia- and TGF-β-related gene signatures were induced in NK cells after PDO co-culture. Deletion of hypoxia inducible factor (HIF)-2a in primary NK cells or blocking of TGF-β-R1 empowered NK cell-mediated PDO killing. We further demonstrate that upon PDO killing, NK cells adopted an activation/inflammationhigh, cytotoxicitylow, tissue-residencyhigh program as evidenced by CXCR6 and CD49a expression coinciding with a “hot” cytokine/chemokine-rich microenvironment. Since PDO-exposed NK cells largely resemble features of NK cells from CRC patient tissues, our NK cell/PDO platform could be highly relevant for the optimization of NK cell products for personalized medicine.

ORGANISM(S): Homo sapiens

PROVIDER: GSE292020 | GEO | 2025/12/17

REPOSITORIES: GEO

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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.

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Colorectal cancer organoids drive patient-specific inflammation, cytotoxicity and tissue-residency programs in NK cells

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