Unraveling exhaustion in adaptive and conventional NK cells

Abstract

Immune exhaustion in T cells significantly impacts their ability to control malignancies and infections, and its discovery has led to revolutionary therapies for cancer in the form of checkpoint blockade. NK cells, like T cells, are lymphocytes that recognize virally infected and malignantly transformed cells. However, it remains unclear if NK cells are similarly susceptible to exhaustion. In this review, the aims are to summarize what is currently known and to identify key areas of variability that skew the scientific literature on NK cell exhaustion. A lack of consensus on the defining features of NK cell dysfunctional states such as senescence, suppression, and exhaustion has made a comparison between studies difficult. There are also significant differences in the biology of NK cell subsets with long-lived, adaptive NK cells sharing an epigenetic signature closer to memory CD8 + T cells than to conventional NK cells. Very different checkpoint receptor expression and effector functions have been shown in adaptive versus conventional NK cells chronically exposed to activating signals. Adaptive NK cells develop in individuals with cytomegalovirus (CMV) infection and well over half of the human population worldwide is CMV seropositive by adulthood. Despite this high prevalence, most studies do not account or control for this population. This may contribute to some of the variability reported in the literature on checkpoint receptor expression on NK cells. In this review, the protective role that exhaustion plays in T cells will also be discussed and the evidence for a similar phenomenon in NK cells will be examined.

Leveraging NKG2D Ligands in Immuno-Oncology

“…This is because CAR-NK cells have several advantages over CAR-T cells such as a shorter half-life (and a subsequent better opportunity to control eventual side effects), a lack of induction of cytokine release syndrome (CRS, often severe and/or fatal in patients that received CAR-T cells), and the possibility of preparing off-the-shelf CAR-NK cells for the treatment of multiple patients ( 28 – 30 ). However, the landscape is quite different for solid tumors mostly because NK cells must face the formidable task of overcoming the immunosuppressive TME to avoid becoming exhausted and dysfunctional ( 31 , 32 ). Also, even if NK cell can overcome this hostile environment, their weak capacity to infiltrate solid tumors is another of the reasons that explain the low success of NK cell-based therapies to treat solid tumors ( 28 , 29 ).…”

Bispecific antibody-mediated redirection of NKG2D-CAR natural killer cells facilitates dual targeting and enhances antitumor activity

“…38 On their own or in combination, ectopic expression of the NKG2D-CAR and application of the bispecific NKAB molecule may also bypass reduced responsiveness and downregulation of endogenous NKG2D observed on chronic stimulation by NKG2DLs and during NK cell exhaustion. [39][40][41] The bispecific NKAB-ErbB2 antibody mimics the general structure of a human IgG molecule, with the hinge, CH2 and CH3 domains of the IgG 4 Fc region separating NKG2D-specific and ErbB2-specific antibody domains. Accordingly, in contrast to other bispecific molecules with only one binding site for NKG2D and a target antigen, [42][43][44] the NKAB-ErbB2 protein was expressed as a homodimer with two binding sites each for NKG2D and ErbB2.…”

Epigenetic Regulation of NK Cell-Mediated Antitumor Immunity

“…This phenotype is represented by a loss of activating receptors (e.g., NKG2D) and increased expression of checkpoint receptors (e.g., NKG2A, TIGIT, PD-1, TIM-3, LAG-3), which severely impair their antitumor function ( 46 ). Compared with the “suppression” state, which is reversible after the withdrawal of inhibitory signaling, the “exhaustion” state is not transient and undergoes stable epigenetic changes ( 47 ). Antagonistic antibodies (Abs) (e.g., anti-PD-1, anti-TIGIT, and anti-NKG2A monoclonal Abs) can recover NK cell antitumor capacity ( 46 , 48 ).…”

“…It is reasonable to presume that NK cells are similar to T cells and show susceptibility to exhaustion during the antitumor war. However, there is a lack of consensus on the defining features of NK cell dysfunctional states, such as senescence, suppression, and exhaustion ( 47 ). Further consideration is needed to determine the state of NK cells in the antitumor response and how their epigenetic landscape changes during the process.…”