Landscape of innate lymphoid cells in human head and neck cancer reveals divergent NK cell states in the tumor microenvironment

Abstract

Natural killer (NK) cells comprise one subset of the innate lymphoid cell (ILC) family. Despite reported antitumor functions of NK cells, their tangible contribution to tumor control in humans remains controversial. This is due to incomplete understanding of the NK cell states within the tumor microenvironment (TME). Here, we demonstrate that peripheral circulating NK cells differentiate down two divergent pathways within the TME, resulting in different end states. One resembles intraepithelial ILC1s (ieILC1) and possesses potent in vivo antitumor activity. The other expresses genes associated with immune hyporesponsiveness and has poor antitumor functional capacity. Interleukin-15 (IL-15) and direct contact between the tumor cells and NK cells are required for the differentiation into CD49a+CD103+ cells, resembling ieILC1s. These data explain the similarity between ieILC1s and tissue-resident NK cells, provide insight into the origin of ieILC1s, and identify the ieILC1-like cell state within the TME to be the NK cell phenotype with the greatest antitumor activity. Because the proportions of the different ILC states vary between tumors, these findings provide a resource for the clinical study of innate immune responses against tumors and the design of novel therapy.

The Dual Role of Innate Lymphoid and Natural Killer Cells in Cancer. from Phenotype to Single-Cell Transcriptomics, Functions and Clinical Uses

“…Very recently, the scRNA-seq of primary tumors, lymph nodes and PBMCs in human head and neck squamous cell carcinoma (HNSCC) patients aimed to reveal the innate immune landscape of this pathology [229]. The analyses, after an unbiased cell assignment of the scRNA-seq clusters, reveal two intratumor NK cell populations with peculiar characteristics.…”

Intraepithelial ILC1-like cells: Front-line fighters in human head and neck squamous cell carcinoma

“…Moreover, one of the two ieILC1-like clusters (cluster 8) is actively proliferating in vivo, as indicated by Ki67 expression, suggesting that ieILC1like cells actively expand in the TME. Moreno-Nieves et al (14) further show that immature peripheral blood CD94 + CD56 bright cells, when exposed to HNSCC cells in the presence of soluble IL-15, multiply and acquire CD103 and CD49a expression. This differentiation process requires cell-cell contact via yet unknown receptor-ligand interactions, as well as TGFβ signaling.…”

“…Moreno-Nieves et al (14), in PNAS, identify in human head and neck squamous cell carcinoma (HNSCC) a cell type closely resembling ieILC1s, which exerts a potent antitumor activity in vitro, and in vivo, in NOD-scid IL2R-gamma null (NSG) immunodeficient mice implanted with a human HNSCC tumor cell line. This cell type has some phenotypic and functional resemblance to a similar previously described NK1.1 + CD103 + CD49a + ILC1-like cell found in mouse models of MMTV-PyMT mammary tumors, which curbs tumor growth due to high cytotoxic potential (15).…”

“…However, their phenotypic and functional heterogeneity was still poorly understood. Moreno-Nieves et al (14), in PNAS, leverage highthroughput single-cell RNA sequencing (scRNAseq) to identify NK cell and related ILC1 subsets from tumors of eight HSNCC cancer patients and compare them to blood-derived NK cells of two healthy donors. Moreno-Nieves et al (14) identify seven clusters of tumor-associated cells that group separately from blood cytotoxic NKs (cluster 1).…”

“…In T cells, NR4A1 and NR4A2 are induced by chronic NFAT stimulation both in models of chronic viral infection and in cancer and are highly expressed in CD8 + T cells bearing multiple inhibitory receptors, such as PD1 and TIM3 (21,22). Whether the NK2 cluster of "exhausted" NK cells, identified by Moreno-Nieves et al (14), behaves similarly to exhausted CD8 + T cells by up-regulating multiple immune checkpoint inhibitors is not clear, possibly due to the relatively shallow number of genes detected by scRNAseq. Cluster 4 has intermediate features between the CD127 + ILC1/CD56 bright and the NK1/2 clusters, again supporting the notion that cells with intermediate features are also present in the TME, in addition to mucosal tissues (4).…”