Abstract
Among the most promising therapeutic modalities for cancer treatment is the blockade of immune checkpoint pathways, which are frequently co-opted by tumors as a major mechanism of immune escape. CTLA-4 and PD-1 are the representative examples, and their blockade by therapeutic antibodies leads to enhanced anti-tumor immunity with durable clinical responses, but only in a minority of patients. This has highlighted the need to identify and target additional immune checkpoints that can be exploited to further enhance immune responses to refractory cancers. These emerging targets include natural killer (NK) cell-directed checkpoint receptors (KIR and CD94/NKG2A) as well as the NK- and T cell-expressed checkpoints TIM-3, TIGIT, CD96, and LAG-3. Interestingly, the potentiation of anti-tumor immunity by checkpoint blockade relies not only on T cells but also on other components of the innate immune system, including NK cells. NK cells are innate lymphoid cells that efficiently kill tumor cells without MHC specificity, which is complementary to the MHC-restricted tumor lysis mediated by cytotoxic T cells. However, the role of these immune checkpoints in modulating the function of NK cells remains unclear and somewhat controversial. Unraveling the mechanisms by which these immune checkpoints function in NK cells and other immune cells will pave the way to developing new therapeutic strategies to optimize anti-tumor immunity while limiting cancer immune escape. Here, we focus on recent findings regarding the roles of immune checkpoints in regulating NK cell function and their potential application in cancer immunotherapy.
Highlights
Natural killer (NK) cells express an array of inhibitory receptors, such as killer immunoglobulin (Ig)-like receptors (KIRs), CD94/NKG2A, programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin- and mucin-domain-containing molecule 3 (TIM-3), T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibition motif (ITIM) domains (TIGIT), CD96, and lymphocyte activation gene 3 (LAG-3) [1,2,3,4,5]
Discovered as a safeguard mechanism to ensure self-tolerance and prevent autoimmunity, immune checkpoint receptors have been explored as attractive therapeutic targets to enhance antitumor immunity, including that mediated by NK cells
As many of these immune checkpoint receptors are not specific to NK cells, it will be important to determine the contribution of NK cells to the clinical benefit of blockade of these molecules
Summary
Natural killer (NK) cells express an array of inhibitory receptors, such as killer immunoglobulin (Ig)-like receptors (KIRs), CD94/NKG2A, programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin- and mucin-domain-containing molecule 3 (TIM-3), T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibition motif (ITIM) domains (TIGIT), CD96, and lymphocyte activation gene 3 (LAG-3) [1,2,3,4,5]. Effective cytotoxicity against tumor cells requires co-engagement of specific activating receptors or pre-activation by cytokines (e.g., IL-2 or IL15) [7]. This additional checkpoint is mediated by common signaling molecules [e.g., c-Cbl, glycogen synthase kinase (GSK)3β, diacylglycerol kinase (DGK)ζ, or cytokine-inducible Src homology-2 (SH2)-containing protein (CIS)] downstream of diverse activating receptors [1], which provides an additional strategy to enhance NK cell reactivity against tumor cells. We focus on inhibitory receptors that serve as checkpoints in human NK cell activation, focusing on the key signaling pathways mediated by these receptors and their clinical relevance
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