Colorectal cancer-infiltrating NK cell landscape analysis unravels tissue-resident PD-1 NK cells in microsatellite instability tumors.

Background: Natural killer (NK) cells are innate lymphocytes endowed with potent cytotoxic activity. The presence of tumor-associated NK cells has been correlated with better prognosis in several solid tumors including colorectal cancer (CRC). This malignant disease is the second cause of cancer death worldwide and is in urgent need for novel approaches to improve current immunotherapies.

CD94-driven expansion of highly functional adaptive NKG2C NKG2A CD57 NK cells from CMV healthy donors.

Background: Adaptive human natural killer (NK) cells are an NK cell subpopulation arising upon cytomegalovirus (CMV) infection. They are characterized by CD94/NKG2C expression, a mature CD57KIRNKG2A phenotype, a prolonged lifespan, and remarkable antitumor functions. In light of these features, adaptive NK cells represent suitable candidate to design next-generation therapies, based on their enhanced effector function which could be further boosted by Chimeric Antigen Receptors-engineering, or the combination with cell engagers.

Pancreatic ductal adenocarcinoma microenvironment: Soluble factors and cancer associated fibroblasts as modulators of NK cell functions.

Pancreatic Ductal Adenocarcinoma (PDAC) is the most frequent pancreatic cancer and represents one of the most aggressive human neoplasms. Typically identified at advance stage disease, most PDAC tumors are unresectable and resistant to standard therapies. The immunosuppressive microenvironment in PDAC impedes tumor control but a greater understanding of the complex stromal interactions within the tumor microenvironment (TME) and the development of strategies capable of restoring antitumor effector immune responses could be crucial to fight this aggressive tumor and its spread.

Early CAR CD4 T-lymphocytes recovery following CAR-T cell infusion: A worse outcome in diffuse large B cell lymphoma.

CAR CD4 T cell lymphopenia is an emerging issue following CAR-T cell therapy. We analyzed the determinants of CD4 T cell recovery and a possible association with survival in 31 consecutive patients treated with commercial CAR-T for diffuse large B-cell (DLBCL) or mantle cell lymphoma. Circulating immune subpopulations were characterized through multiparametric-flow cytometry.

Identification of a novel cord blood NK cell subpopulation expressing functional programmed death receptor-1.

Background: Natural Killer cells (NKs) represent the innate counterpart of TCRαβ lymphocytes and are characterized by a high anti-tumor and an anti-viral cytotoxic activity. Recently, it has been demonstrated that NKs can express PD-1 as an additional inhibitory receptor. Specifically, PD-1 was identified on a subpopulation of terminally differentiated NKs from healthy adults with previous HCMV infection.

NK Cell-Based Immunotherapy in Colorectal Cancer.

Human Natural Killer (NK) cells are all round players in immunity thanks to their powerful and immediate response against transformed cells and the ability to modulate the subsequent adaptive immune response. The potential of immunotherapies based on NK cell involvement has been initially revealed in the hematological setting but has inspired the design of different immune tools to also be applied against solid tumors, including colorectal cancer (CRC). Indeed, despite cancer prevention screening plans, surgery, and chemotherapy strategies, CRC is one of the most widespread cancers and with the highest mortality rate.

CD19-Targeted Immunotherapies for Diffuse Large B-Cell Lymphoma.

Surgical resection, chemotherapy and radiotherapy were, for many years, the only available cancer treatments. Recently, the use of immune checkpoint inhibitors and adoptive cell therapies has emerged as promising alternative. These cancer immunotherapies are aimed to support or harness the patient's immune system to recognize and destroy cancer cells.

Role of the Main Non HLA-Specific Activating NK Receptors in Pancreatic, Colorectal and Gastric Tumors Surveillance.

Human NK cells can control tumor growth and metastatic spread thanks to their powerful cytolytic activity which relies on the expression of an array of activating receptors. Natural cytotoxicity receptors (NCRs) NKG2D and DNAM-1 are those non-HLA-specific activating NK receptors that are mainly involved in sensing tumor transformation by the recognition of different ligands, often stress-induced molecules, on the surface of cancer cells. Tumors display several mechanisms aimed at dampening/evading NK-mediated responses, a relevant fraction of which is based on the downregulation of the expression of activating receptors and/or their ligands.

NK cells as adoptive cellular therapy for hematological malignancies: Advantages and hurdles.

Natural killer cells are an essential component of the innate immune system and play a crucial role in immunity against malignancies, without, at difference with T cells, requiring antigen priming or inducing graft-versus-host-disease. Hence, Natural Killer cells can provide a valuable source of allogeneic "off-the-shelf" adoptive therapy and mediate major antileukemia effects, without inducing potentially lethal alloreactivity. Several cell sources have been used for producing and expanding large numbers of clinical-grade natural killer cells.

Inhibitory Receptors and Checkpoints in Human NK Cells, Implications for the Immunotherapy of Cancer.

The highly destructive mechanisms by which the immune system faces microbial infections is under the control of a series of inhibitory receptors. While most of these receptors prevent unwanted/excessive responses of individual effector cells, others play a more general role in immunity, acting as true inhibitory checkpoints controlling both innate and adaptive immunity. Regarding human NK cells, their function is finely regulated by HLA-class I-specific inhibitory receptors which allow discrimination between HLA-I, healthy cells and tumor or virus-infected cells displaying loss or substantial alterations of HLA-I molecules, including allelic losses that are sensed by KIRs.

Natural killer cell impairment in ovarian clear cell carcinoma.

In the present study, we report the analysis of NK cells derived from patients suffering from a rare ovarian cancer histotype of clear cell carcinoma (OCCC) resistant to conventional chemotherapies. We analyzed the phenotype of NK cells derived from peripheral blood (PB) and peritoneal fluid (PF) and evaluated cytotoxic interactions between NK cells and autologous tumor cells (ATC) derived from patients. We provided evidence of impaired degranulation capacity of NK cells derived from patients' PF in the presence of ATC.

miRNAs in NK Cell-Based Immune Responses and Cancer Immunotherapy.

The incidence of certain forms of tumors has increased progressively in recent years and is expected to continue growing as life expectancy continues to increase. Tumor-infiltrating NK cells may contribute to develop an anti-tumor response. Optimized combinations of different cancer therapies, including NK cell-based approaches for targeting tumor cells, have the potential to open new avenues in cancer immunotherapy.

NK Cell-Based Immunotherapy for Hematological Malignancies.

Natural killer (NK) lymphocytes are an integral component of the innate immune system and represent important effector cells in cancer immunotherapy, particularly in the control of hematological malignancies. Refined knowledge of NK cellular and molecular biology has fueled the interest in NK cell-based antitumor therapies, and recent efforts have been made to exploit the high potential of these cells in clinical practice. Infusion of high numbers of mature NK cells through the novel graft manipulation based on the selective depletion of T cells and CD19 B cells has resulted into an improved outcome in children with acute leukemia given human leucocyte antigen (HLA)-haploidentical hematopoietic transplantation.

Different Features of Tumor-Associated NK Cells in Patients With Low-Grade or High-Grade Peritoneal Carcinomatosis.

Peritoneal carcinomatosis (PC) is a rare disease defined as diffused implantation of neoplastic cells in the peritoneal cavity. This clinical picture occurs during the evolution of peritoneal tumors, and it is the main cause of morbidity and mortality of patients affected by these pathologies, though cytoreductive surgery with heated intra-peritoneal chemotherapy (CRS/HIPEC) is yielding promising results. In the present study, we evaluated whether the tumor microenvironment of low-grade and high-grade PC could affect the phenotypic and functional features and thus the anti-tumor potential of NK cells.

An Historical Overview: The Discovery of How NK Cells Can Kill Enemies, Recruit Defense Troops, and More.

Natural killer (NK) cells were originally defined as effector lymphocytes of innate immunity characterized by the unique ability of killing tumor and virally infected cells without any prior priming and expansion of specific clones. The "missing-self" theory, proposed by Klas Karre, the seminal discovery of the first prototypic HLA class I-specific inhibitory receptors, and, later, of the Natural Cytotoxicity Receptors (NCRs) by Alessandro Moretta, provided the bases to understand the puzzling behavior of NK cells. Actually, those discoveries proved crucial also for many of the achievements that, along the years, have contributed to the modern view of these cells.

KIR3DS1-Mediated Recognition of HLA-*B51: Modulation of KIR3DS1 Responsiveness by Self HLA-B Allotypes and Effect on NK Cell Licensing.

Several studies described an association between killer-cell immunoglobulin-like receptor (KIR)/HLA gene combinations and clinical outcomes in various diseases. In particular, an important combined role for KIR3DS1 and HLA-B Bw4-I80 in controlling viral infections and a higher protection against leukemic relapses in donor equipped with activating KIRs in haplo-HSCT has been described. Here, we show that KIR3DS1 mediates positive signals upon recognition of HLA-B*51 (Bw4-I80) surface molecules on target cells and that this activation occurs only in Bw4-I80 individuals, including those carrying particular KIR/HLA combination settings.

Features of Memory-Like and PD-1(+) Human NK Cell Subsets.

Human NK cells are distinguished into CD56(bright)CD16(-) cells and CD56(dim)CD16(+) cells. These two subsets are conventionally associated with differential functional outcomes and are heterogeneous with respect to the expression of KIR and CD94/NKG2 heterodimers that represent the two major types of HLA-class I-specific receptors. Recent studies indicated that immature CD56(bright) NK cells, homogeneously expressing the inhibitory CD94/NKG2A receptor, are precursors of CD56(dim) NK cells that, in turn, during their process of differentiation, lose expression of CD94/NKG2A and subsequentially acquire inhibitory KIRs and LIR-1.

Activating KIRs and NKG2C in Viral Infections: Toward NK Cell Memory?

Natural killer (NK) cells are important players in the immune defense against viral infections. The contribution of activating killer immunoglobulin-like receptors (KIRs) and CD94/NKG2C in regulating anti-viral responses has recently emerged. Thus, in the hematopoietic stem cell transplantation setting, the presence of donor activating KIRs (aKIRs) may protect against viral infections, while in HIV-infected individuals, KIR3DS1, in combination with HLA-Bw4-I80, results in reduction of viral progression.

Uptake of CCR7 by KIR2DS4⁺ NK cells is induced upon recognition of certain HLA-C alleles.

The KIR2DS4 receptor is the oldest KIR2DS expressed by human NK lymphocytes. The specificity of recognition of this receptor for various HLA class I alleles has been demonstrated; however it remains poorly understood whether these interactions may result in the activation of some specific functions in NK cells. Here, we examined the functional outcome of the KIR2DS4/HLA class I interaction by the use of an alternative functional system based on the ability of KIR2DS4 to regulate the mechanism of trogocytosis by NK cells.

TLR/NCR/KIR: Which One to Use and When?

By means of a complex receptor array, Natural killer (NK) cells can recognize variable patterns of ligands and regulate or amplify accordingly their effector functions. Such NK receptors include old, rather conserved, molecules, such as toll-like receptors (TLRs), which enable NK cells to respond both to viral and bacterial products, and newer and evolving molecules, such as killer Ig-like receptors and natural cytotoxicity receptors, which control NK cytotoxicity and are responsible for the elimination of virus-infected or tumor cells without damaging self-unaltered cells. In addition, to rapidly gain new functions NK cells also can acquire new receptors by trogocytosis.

Human NK cell response to pathogens.

NK cells represent important effectors of the innate immunity in the protection of an individual from microbes. During an NK-mediated anti-microbial response, the final fate (survival or death) of a potential infected target cell depends primarily on the type and the number of receptor/ligand interactions occurring at the effector/target immune synapse. The identification of an array of receptors involved in NK cell triggering has been crucial for a better understanding of the NK cell biology.

KIR2DS1-dependent acquisition of CCR7 and migratory properties by human NK cells interacting with allogeneic HLA-C2+ DCs or T-cell blasts.

Natural killer (NK) cells may capture the CCR7 chemokine receptor from allogeneic CCR7(+) cells by trogocytosis and acquire migrating properties in response to lymph node chemokines. This event is negatively regulated by inhibitory killer Ig-like receptors (KIRs) and NKG2A. In this study, we analyzed the role of the HLA-C2-specific activating receptor KIR2DS1 in the process of CCR7 uptake by NK cells interacting with different allogeneic CCR7(+) cells.

NK/DC crosstalk in anti-viral response.

In recent years, it has been emphasized the role of the crosstalk between natural killer (NK) cells and monocyte-derived dendritic cells dendritic cells (moDCs) in the regulation of the early phases of innate immunity innate immunity and of the subsequent adaptive immune responses. NK cells and DCs coordinate their response communicating through direct cell-to-cell contact and soluble factors. NK cells appear to contribute to the quality control of immature DCs (iDCs) undergoing maturation.

NK cells and their receptors during viral infections.

Increasing evidence indicates the importance of human natural killer (NK) cells in the immune response against certain viral infections. In the present article, we summarize information on NK cell responses against several viruses and on the nature of NK cell receptor-ligand interactions involved in these responses. Recent studies indicate that NK cells display functional features that are normally attributed exclusively to cells of the adaptive immune system.