Innate Lymphoid Cells in Cancer: Friends or Foes?

Innate Lymphoid Cells (ILCs) are the most recently identified innate immune cell types and are composed of 5 distinct subsets. These include NK cells, ILC1, ILC2, ILC3 and Lymphoid Tissue inducer (LTi) cells. Unlike T and B cells, ILC activity does not rely on the expression of specific receptors but rather depends on the integration of multiple surrounding inhibitory and activation signals. In particular, they express a wide range of cytokine receptors and immune checkpoints that modulate their functions. Often seen as the innate counterpart of T cells, they express similar transcription factors and cytokines. Whilst NK cells are analogous to cytotoxic CD8 T cells, ILC1, ILC2 and ILC3 are often compared to the helper Th1, Th2 and Th17 cells, respectively. NK cells and ILC1 express T-bet and secrete IFNγ, while ILC2 are characterized by the expression of GATA3 and the production of IL-4, IL-5, IL-13 and amphiregulin, and ILC3 and LTi universally express RORγt and produce IL-17A and IL-22. ILCs are rapidly responding cells that exhibit potent immunomodulatory properties, thus making them essential regulators of tissue inflammation and homeostasis. When uncontrolled, this inflammatory response may lead to the development of allergy and autoimmune diseases or may contribute to the immune tumor responses.

Tumors form a complex and heterogeneous microenvironment with distinct immune cell types that includes ILCs. NK cells are efficient at killing diverse tumor cell types, and some of the clinical approaches used to boost the T cell cytotoxicity may also promote NK cell response. Recent works suggest that non-NK ILC subsets play also a role in tumorigenesis. These cells are shown to influence the tumor initiation, development, and tumor dissemination. However, their contribution towards immune protection or tumor promotion appears to depend on the tumor origin and disease stage suggesting that, the tumor microenvironment dictates fate of tumor-infiltrating ILC. Understanding these features is of extreme importance as it may provide new therapeutic avenues to rewire the immune response for the establishment of an early and appropriate anti-tumor immunity. The function of these cells in fighting tumors is currently being actively explored.

In this Research Topic, we aim to provide a current overview of the field with original contributions about the function, regulatory mechanisms and prognostic roles of ILCs in cancer and their impact on therapeutic responses and clinical outcomes. We welcome the submission of Original Research articles, Reviews and Perspectives about the role of Innate Lymphoid Cells in human malignancies and pre-clinical tumor models.