Multidimensional molecular controls defining NK/ILC1 identity in cancers

Innate Lymphoid Cells (ILCs) are a recently described heterogeneous population of non-T, non-B lymphocytes. They are highly abundant at mucosal interfaces and, unlike T and B cells, they do not express somatically rearranged antigen-specific receptors. ILCs may be seen as the innate counterparts of T cells, but, major ILC deficiencies in humans appear to be clinically silent in modern conditions of hygiene and medicine, provided that T and B functions are preserved. NK cells are the founder members of this family and were originally classified in group 1 ILCs with ILC1s, due to similarities in cytokine production and development between these two types of cell. The classification of the ILC subsets was subsequently reviewed and five groups were defined on the basis of cytokine production and the discovery of specific transcription factors determining the different lineages. ILCs include NK cells, lymphoid tissue-inducer (LTi) cells and three other main subsets: ILC1s, ILC2s and ILC3s. The nature of distinct ILC1 population in mice and human is not consensual due to the high degree of similarity between ILCs and NK cells and their plastic relationships in some context. In this review, we will discuss the characteristics currently used for the phenotyping of NK cells and ILC1s in mice and humans, in the context of cancers especially, in which inappropriate discrimination between these two cell types can lead to erroneous conclusions regarding the specific impact of their targeting on tumors. Here, we suggest that multidimensional molecular controls, with the co-ordination of ontogeny-related signals, tissue-specific and tumor microenvironment-derived signals, determine the identity of NK cells and ILC1s. All these molecular stratifications contribute to the construction of cell fate for NK cells and ILC1s and account for the difficulties distinguishing between these two groups of cells.