Human NK cells: surface receptors, inhibitory checkpoints, and translational applications

Abstract

NK cells play important roles in innate defenses against viruses and in the control of tumor growth and metastasis. The regulation/ induction of NK cell function is mediated by an array of activating or inhibitory surface receptors. In humans, major activating receptors involved in target cell killing are the natural cytotoxicity receptors (NCRs) and NKG2D. Activating receptors recognize ligands that are overexpressed or expressed de novo upon cell stress, viral infection, or tumor transformation. The HLA-class Ispecific inhibitory receptors, including KIRs recognizing HLA-class I allotypic determinants and CD94/NKG2A recognizing the class-Ib HLA-E, constitute a fail-safe mechanism to avoid unwanted NK-mediated damage to healthy cells. Other receptors such as PD-1, primarily expressed by activated T lymphocytes, are important inhibitory checkpoints of immune responses that ensure T-cell tolerance. PD-1 also may be expressed by NK cells in cancer patients. Since PD-1 ligand (PD-L1) may be expressed by different tumors, PD-1/PD-L1 interactions inactivate both T and NK cells. Thus, the reliable evaluation of PD-L1 expression in tumors has become a major issue to select patients who may benefit from therapy with mAbs disrupting PD-1/PD-L1 interactions. Recently, NKG2A was revealed to be an important checkpoint controlling both NK and T-cell activation. Since most tumors express HLA-E, mAbs targeting NKG2A has been used alone or in combination with other therapeutic mAbs targeting PD-1 or tumor antigens (e.g., EGFR), with encouraging results. The translational value of NK cells and their receptors is evidenced by the extraordinary therapeutic success of haploidentical HSCT to cure otherwise fatal high-risk leukemias.

Age-associated changes in the immune system may influence the response to anti-PD1 therapy in metastatic melanoma patients

“…Anti-PD1 monoclonal antibodies are designed to inhibit the inactivating binding of the programmed death-ligand 1 (PD-L1), by binding to the PD-1 receptor on the surface of an activated T cell, thus enabling the antitumor immune response by T cells [5]. PD1 expression on NK cells has been previously described in cancer patients and human cytomegalovirus (HCMV) seropositive healthy individuals, and similarly to CD8 + T cells, high PD1 expression on NK cells has been characterized as a sign of exhaustion, with lower degranulation or cytotoxic activity and cytokine production compared to PD1 neg NK cells [25][26][27][28]. Our results were in line with the previous observations that besides PB T cells, PB NK and NKT cells also express PD1 receptors on their surface, supporting our hypothesis that these cells may play an important role in the anti-PD1-mediated antitumor effect for metastatic melanoma patients.…”

Targeting Natural Killer Cells for Tumor Immunotherapy

“…Similarly, a variety of immune checkpoints receptors are expressed in NK cells, including KIRs, NKG2A, T-cell immunoglobulinand mucin-domain-containing molecule 3, programmed cell death 1 (PD-1), lymphocyte activation gene-3, and T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT). These inhibitory receptors are often induced or upregulated on tumor-infiltrating NK cells and affect the antitumor function of NK cells upon interaction with their respective ligands, even leading to dysfunction or exhaustion of NK cells (113). Functionally exhausted NK cells show less proliferation, reduced cytolytic activity, and downregulated cytokine secretion, thus losing the ability to attack tumor cells.…”

“…The interim results of the phase II trial for treatment efficacy showed that combination therapy comprising IPH2201 and Cetuximab resulted in 31% partial response, 54% stable disease, and 11% progressive disease (118). Therefore, anti-NKG2A mAbs are proposed as promising checkpoint inhibitors that could enhance antitumor immunity via unleashing the potential of both T and NK cells (113,119).…”

Increased expression of activating receptors and up-regulated function of natural killer cells in peripheral blood of patients with HBV-related hepatocellular carcinoma

“…However, CD56 bright NK cells represent only ~ 10% in peripheral blood but predominate in tissues. These cells are minority cytolytic but e ciently secrete cytokines [21]. Certain cytokines (IL-12/15/18) have been assumed to control the function of NK cells.…”