Plasticity and Polarization of Human NK Cells in the Tumor Microenvironment

Abstract

Abstract The presence and function of innate lymphoid cells (ILC), including natural killer (NK) cells, within human tumors has been poorly characterized. Here, we have assessed the heterogeneity of NK and ILC populations by single-cell RNA sequencing (scRNAseq) of hundreds of individual NK cells and ILCs within human head and neck squamous cell carcinoma (HNSCC), matched lymph node metastases, matched peripheral blood, and blood from healthy donors. Fresh tumor specimens and blood were obtained from 8 patients undergoing surgical resection of HNSCC. Unsupervised clustering revealed 8 different clusters of NK cells and ILC subsets. We observed significant heterogeneity, with distinct subsets showing profiles consistent with that of conventional NK cells, ILC1-like cells and ILC3-like cell. Importantly, peripheral NK cells were distinct from intratumoral NK cells. The presence of these different cell subsets within primary HNSCC tumors was confirmed by flow cytometry. Further, plasticity between the NK cell subsets was supported by in vitro and in vivo experimental data. Given the ability of NK and ILCs to polarize the immune responses through the secretion of cytokines and the ability of certain subsets to kill target cells, we hypothesize that the differences observed in NK and ILC populations and their plasticity may result in different immune responses, and may influence clinical outcomes following therapy.