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Receptor activator of nk b for tumor cells

Recognition of tumors by the innate immune system and natural killer cells

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To view a copy of this license, visit http: Abstract Natural killer NK cells have gained considerable attention as promising therapeutic tools for cancer therapy due to their innate selectivity against cancer cells over normal healthy cells. With an array of receptors evolved to sense cellular alterations, NK cells provide early protection against cancer cells by producing cytokines and chemokines and exerting direct cytolytic activity.

These effector functions are governed by signals transmitted through multiple receptor—ligand interactions but are not achieved by engaging a single activating receptor on resting NK cells. Rather, they require the co-engagement of different activating receptors that use distinct signaling modules, due to a cell-intrinsic inhibition mechanism.

The redundancy of synergizing receptors and the inhibition of NK cell function by a single class of inhibitory receptor suggest the presence of common checkpoints to control NK cell activation through different receptors.

These molecular checkpoints would be therapeutically targeted to harness the power of NK cells against diverse cancer cells that express heterogeneous ligands for NK cell receptors. Recent advances in understanding the activation of NK cells have revealed promising candidates in this category.

Targeting such molecular checkpoints will facilitate NK cell activation by lowering activation thresholds, thereby providing therapeutic strategies that optimize NK cell reactivity against cancer. In support, numerous studies have demonstrated that NK cell functional deficiency is associated with an increased risk of developing various types of cancer, 567 including a seminal 11-year follow-up study reporting the high receptor activator of nk b for tumor cells of cancer incidence in subjects with low NK cell cytotoxic activity.

  1. Two ligands for DNAM-1 have been identified in humans and mice.
  2. Furthermore, CCL2 neutralization, but not neutralization of the other chemokines, resulted in delayed elimination of the senescent tumor cells, providing direct evidence that p53-induced CCL2 expression was responsible for NK cell recruitment and senescent tumor elimination.
  3. When the capacity of NK cells to mediate tumor rejection is overwhelmed, perhaps because the tumor is well advanced at the time that it is infiltrated, the persistent stimulation of the NK cells drives them into a hyporesponsive state. In seeking an explanation for why the NK cells failed to eliminate RAE-1-expressing nonsenescent tumor cells, it was noted that very few NK cells infiltrated such growing tumors, whereas many NK cells infiltrated senescent tumor cells in which p53-expression had been induced.
  4. The identity of the tumor cell ligands for these receptors is a matter of ongoing research, but candidates have emerged over recent years. NCRs are also involved in the process of discriminating between self and non-self via the generically termed MHC I receptor and ligand 7 , 8.

NK cells are equipped with an array of germline-encoded surface receptors that recognize specific ligands on target cells and use diverse receptor combinations to deliver selective cytotoxicity against cancer cells. Thus, the decision of an NK cell to kill target cells is determined by a signaling balance between activating and inhibitory receptors.

Natural killer cell

Except for CD16-mediated antibody-dependent cellular cytotoxicity, NK cell effector functions are rarely triggered by engaging a single activating receptor on human, freshly isolated resting NK cells. Rather, their activation requires the co-engagement of specific pairs of activating receptors with distinct signaling properties.

Thus, understanding how signals from different activating receptors converge on common molecular checkpoints is important and may provide innovative strategies that enhance NK cell activation for cancer immunotherapy.

Moreover, upon exposure to cytokines for example, interleukin IL -2 or IL-15NK cells have enhanced survival and reactivity toward target cells. Such cytokine stimulation lowers the threshold for NK cell activation and thereby renders NK cells responsive to a single activating receptor for example, NKG2D to trigger effector functions. Initially developed for T-cell-based therapy, blockade of immune checkpoints for example, PD-1 and chimeric antigen receptors CARs also show promising results when applied to NK-cell-based cancer therapy.

Due to our advanced understanding of NK cell activation, many efforts have been made to enhance the therapeutic benefit of NK cells via manipulation of effector functions. In this review, we describe recent progress in NK cell activation and discuss therapeutic strategies targeting NK cells, with a focus on common signaling checkpoints for different activating receptors. Common signaling checkpoints for NK cell activation Compared to T cells that are dominantly activated by immunoreceptor tyrosine-based activation motif ITAM -coupled TCR, NK cells have a multitude of receptors with different ligand specificity and signaling properties for activation: