Tumor-infiltrating immature innate lymphoid cells in colorectal cancer are biased toward ILC1/tissue-resident NK cell differentiation
Anne Marchalot, Malin Ljunggren, Christopher Stamper, Whitney Weigel, Christopher Andrew Tibbitt, Isabel Meininger, Ram Vinay Pandey, Miriam Franklin, John Washington Bassett, Lorenz Wirth, Unknown, Ali Kiasat, Anders Hansson Elliot, Carl Kördel, Emma Rosander, Henrik Iversen, Madelene Ahlberg, Mirna Abraham Nordling, Petri Rantanen, Richard Marsk, Stefan Carlens, Ulf O. Gustafsson, Ulrik Lindforss, Gabriella Jansson-Palmer, Caroline Nordenvall, Jenny Mjösberg
Abstract
Abstract 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.