Innate Lymphoid Cells: Expression of PD-1 and Other Checkpoints in Normal and Pathological Conditions

Abstract

Innate lymphoid cells (ILCs) belong to a family of immune cells. Recently, ILCs have been classified into five different groups that mirror the function of adaptive T cell subsets counterparts. In particular, NK cells mirror CD8⁺ cytotoxic T cells while ILC1, ILC2, ILC3, and Lymphoid tissue inducer (LTi)-like cells reflect the function of CD4⁺T helper (Th) cells (Th1, Th2, and Th17 respectively). ILCs are involved in innate host defenses against pathogens and tumors, in lymphoid organogenesis, and in tissue remodeling/repair. In recent years, important molecular inducible checkpoints (PD-1, TIM3, and TIGIT) were shown to control/inactivate different immune cell types. The expression of many of these receptors has been detected on NK cells and subsets of tissue-resident ILCs in both physiological and pathological conditions, including cancer. In particular, it has been demonstrated that the interaction between PD-1⁺ immune cells and PD-L1/PD-L2+ tumor cells may compromise the anti-tumor effector function leading to tumor immune escape. However, while the effector function of NK cells in tumor is well-established, limited information exists on the other ILC subsets. We will summarize what is known to date on the expression and function of these checkpoint receptors on NK cells and ILCs, with a particular focus on the recent data that reveal an essential contribution of the blockade of PD-1 and TIGIT on NK cells to the immunotherapy of cancer. A better information regarding the presence and the function of different ILCs and of the inhibitory checkpoints in pathological conditions may offer important clues for the development of new immune therapeutic strategies.

Keywords: ILC; NK; PD-1; cancer immunotherapies; checkpoint receptors.

Figure 1

Current view of differentiation and immune function of ILC subsets. ILCs originate from common lymphoid progenitors (CLPs) that give rise to common innate lymphoid progenitors (CILPs). On one side, CILPs can differentiate into NK precursor (NKP) that, through T-bet and Eomes, will originate NK cells, and on the other side into common helper innate lymphoid precursors (CHILP) from which originate both Innate lymphoid precursors (ILP) and lymphoid tissue inducer progenitors (LTiP). ILC1/2/3 subsets and LTi cells differentiate, according to the different transcription factors required, from ILP and LTiP precursors, respectively. As specified in the text, NK/ILC cells release various cytokines and exert different immune functions.

Figure 2

Schematic representation of checkpoint receptors and their ligands expressed by ILC and tumor cells, respectively. NK cells express multiple immune checkpoint receptors, such as PD-1, TIM-3, Lag-3, TIGIT, and CD96. ON the other hand, these checkpoint receptors are instead differentially expressed by ILC subsets. Thus, TIGIT and TIM-3 have been detected only on ILC1 cells, while CD96 is expressed on both ILC1 and ILC2. Surface expression of KLRG1 and PD-1 appears to be restricted to ILC2 cells. The inhibitory ligands expressed by tumor cells, specifically interact with the checkpoint receptors preventing cells activation. However, different therapeutic approaches, aimed to block receptor/ligand interactions, have been demonstrated to restore the anti-tumor activity of immune cells, as illustrated in the Figure. The solid and dotted arrows indicate the strong and weak binding affinity of TIGIT for the different ligands, respectively.