Tumor-infiltrating immature innate lymphoid cells in colorectal cancer are biased toward ILC1/tissue-resident NK cell differentiation
Peritoneal metastases (PM) occur in 10% of patients with colorectal cancer (CRC) and are linked to poor outcomes. Although dysregulated innate lymphoid cells (ILC) have been described in CRC, their function in CRC-PM remains unclear. Here, we analyze tumor samples from CRC and CRC-PM patients using single-cell RNA sequencing (11 patients), flow cytometry (8 patients) and differentiation assays (24 patients). Healthy colon, primary CRC and CRC-PM tumors are infiltrated by heterogeneous populations of ILC3, ILC2, ILC1, tissue resident (tr)NK cells and conventional (c)NK cells. Compared to healthy colons, primary CRC and CRC-PM tumors are depleted of ILC3 but enriched for ILC1, trNK cells and cNK cells. CRC and CRC-PM tumors harbor two immature ILC populations, early NK and naïve (n)ILC, with nILCs being transcriptionally skewed toward ILC1 and trNK cells. Indeed, co-culture of isolated nILCs with OP9-DL1 cells induces intratumoral nILC differentiation into ILC1/trNK-like cells. These findings help understand the immune pathogenesis of CRC and CRC-PM and provide insights for future ILC1 and NK cell-based therapies.
Authors
- Carl Kördel
- Richard Marsk (ORCID: https://orcid.org/0000-0001-9814-3357)
- Isabel Meininger (ORCID: https://orcid.org/0000-0001-7562-8853)
- Ulrik Lindforss (ORCID: https://orcid.org/0000-0003-4239-8419)
- Malin Ljunggren (ORCID: https://orcid.org/0000-0001-9297-1573)
- Ulf Gustafsson (ORCID: https://orcid.org/0000-0001-9549-061X)
- Petri Rantanen (ORCID: https://orcid.org/0000-0001-8623-6652)
- Emma Rosander (ORCID: https://orcid.org/0000-0003-0825-0605)
- Henrik Iversen (ORCID: https://orcid.org/0000-0002-6918-5854)
- Stefan Carlens
- Miriam Franklin (ORCID: https://orcid.org/0000-0002-9402-9976)
- Christopher T. Stamper (ORCID: https://orcid.org/0000-0002-5568-8880)
- Lorenz Wirth (ORCID: https://orcid.org/0000-0003-4795-7814)
- Anne Marchalot (ORCID: https://orcid.org/0000-0002-3042-8206)
- Christopher A. Tibbitt (ORCID: https://orcid.org/0000-0002-7730-7700)
- Anders H. Elliot (ORCID: https://orcid.org/0000-0001-5853-0213)
- Mirna Abraham Nordling
- Ram Vinay Pandey (ORCID: https://orcid.org/0000-0001-7420-4346)
- Caroline A.M. Nordenvall (ORCID: https://orcid.org/0000-0002-5112-8894)
- Jenny Mjösberg (ORCID: https://orcid.org/0000-0002-1119-0976)
- Whitney Weigel (ORCID: https://orcid.org/0000-0003-2218-4026)
- Gabriella Jansson-Palmer
- Ali Kiasat (ORCID: https://orcid.org/0000-0001-5568-3265)
- Madelene Ahlberg
- Colorectal Study Group
- John Washington Bassett
Institutions
- Karolinska University Hospital (SE)
- Karolinska Institutet (SE)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-03-27
- DOI
- https://doi.org/10.1038/s41467-026-71085-9
- Primary Topic
- IL-33, ST2, and ILC Pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.00