Immunotherapy targeting inhibitory checkpoints: The role of NK and other innate lymphoid cells.

Monoclonal antibodies that target specific ligand-receptor signaling pathways and act as immune checkpoint inhibitors have been designed to remove the brakes in T cells and restore strong and long-term antitumor-immunity. Of note, many of these inhibitory receptors are also expressed by Innate Lymphoid Cells (ILCs), suggesting that also blockade of inhibitory pathways in innate lymphocytes has a role in the response to the treatment with checkpoint inhibitors. ILCs comprise cytotoxic NK cells and "helper" subsets and are important cellular components in the tumor microenvironment. In addition to killing tumor cells, ILCs release inflammatory cytokines, thus contributing to shape adaptive cell activation in the context of immunotherapy. Therefore, ILCs play both a direct and indirect role in the response to checkpoint blockade. Understanding the impact of ILC-mediated response on the treatment outcome would contribute to enhance immunotherapy efficacy, as still numerous patients resist or relapse.

Glucocorticoids inhibit human hematopoietic stem cell differentiation toward a common ILC precursor.

BACKGROUND: Innate lymphoid cells (ILCs) comprise cytotoxic natural killer (NK) cells and helper ILCs (hILCs). Human hILC development is less characterized as compared with that of NK cells, although all ILCs are developmentally related. It has been reported that the immunosuppressive drugs glucocorticoids (GCs) regulate ILC function, but whether they control ILC differentiation from hematopoietic stem cells (HSCs) is unknown. OBJECTIVES: This study sought to analyze the effect of GCs on ILC development from HSCs. METHODS: This study exploited an in vitro system to generate and expand from peripheral blood HSCs a multipotent CD56+ ILC precursor able to differentiate into NK cells, ILC1s, and ILC3s. We also analyzed ex vivo, at different time points, the peripheral blood of recipients of allogeneic HSC transplantation who were or were not treated with GCs and compared ILC subset reconstitution. RESULTS: Invitro, GCs favor the generation of NK cells from myeloid precursors, while they strongly impair lymphoid development. In support of these data, recipients of HSC transplantation who had been treated with GCs display a lower number of circulating hILCs, including the ILC precursor (ILCP) previously identified as a systemic substrate for tissue ILC differentiation. CONCLUSIONS: GCs impair the development of the CD117+ ILCP from CD34+ HSCs, while they do not affect the further steps of ILCP differentiation toward NK cells and hILC subsets. This reflects an association of GC treatment with a marked reduction of circulating hILCs in the recipients of HSC transplantation.

Regulation of the Immune System Development by Glucocorticoids and Sex Hormones.

Through the release of hormones, the neuro-endocrine system regulates the immune system function promoting adaptation of the organism to the external environment and to intrinsic physiological changes. Glucocorticoids (GCs) and sex hormones not only regulate immune responses, but also control the hematopoietic stem cell (HSC) differentiation and subsequent maturation of immune cell subsets. During the development of an organism, this regulation has long-term consequences. Indeed, the effects of GC exposure during the perinatal period become evident in the adulthood. Analogously, in the context of HSC transplantation (HSCT), the immune system development starts de novo from the donor HSCs. In this review, we summarize the effects of GCs and sex hormones on the regulation of HSC, as well as of adaptive and innate immune cells. Moreover, we discuss the short and long-term implications on hematopoiesis of sex steroid ablation and synthetic GC administration upon HSCT.