Natural killer (NK) cells are innate lymphoid cells endowed with cytolytic activity and a capacity to secrete cytokines and chemokines. Several lines of evidence suggest that NK cells play an ...important role in anti-tumor immunity. Some therapies against hematological malignacies make use of the immune properties of NK cells, such as their ability to kill residual leukemic blasts efficiently after conditioning during haploidentical hematopoietic stem cell transplantation. However, knowledge on NK cell infiltration and the status of NK cell responsiveness in solid tumors is limited so far. The pro-angiogenic role of the recently described NK cell-like type 1 innate lymphoid cells (ILC1s) and their phenotypic resemblance to NK cells are confounding factors that add a level of complexity, at least in mice. Here, we review the current knowledge on the presence and function of NK cells in solid tumors as well as the immunotherapeutic approaches designed to harness NK cell functions in these conditions, including those that aim to reinforce conventional anti-tumor therapies to increase the chances of successful treatment.
Monocytes can have important effects on the polarization and expansion of lymphocytes and may contribute to shaping primary and memory T-cell responses in humans and mice. However, their precise ...contribution in terms of cellular subsets and the molecular mechanisms involved remains to be determined. Mouse monocytes originate from a bone marrow progenitor, the macrophage and DC precursor (MDP), which also gives rise to conventional dendritic cells through a separate differentiation pathway. Mouse monocytes may be grouped in different functional subsets. The CD115(+) Gr1(+) 'inflammatory' monocyte subset can give rise not only to immunostimulatory 'TipDCs' in infected mice but also to immunosuppressive 'myeloid-derived suppressor cells' in tumor-bearing mice. CD115(+) Gr1(+) monocytes can also contribute to the renewal of several resident subsets of macrophages and DCs, such as microglia and Langerhans cells, in inflammatory conditions. The CD115(+) Gr1(-) 'resident' monocyte subset patrols blood vessels in the steady state and extravasates during infection with Listeria monocytogenes or in the healing myocardium. CD115(+) Gr1(-) monocytes are responsible for an early and transient inflammatory burst during Lm infection, which may play a role in the recruitment of other effector cells and subsequently differentiate toward 'M2'-like macrophages that may be involved in wound healing. More research will no doubt confirm the existence of more functional subsets, the developmental relationship between mouse subsets as well as the correspondence between mouse subsets and human subsets of monocytes. We will discuss here the potential roles of monocytes in the immune response, the existence of functional subsets and their relationship with other myeloid cells, including dendritic cells.
Natural killer (NK) cells are innate lymphoid cells (ILCs) involved in antimicrobial and antitumoral responses. Several NK cell subsets have been reported in humans and mice, but their heterogeneity ...across organs and species remains poorly characterized. We assessed the diversity of human and mouse NK cells by single-cell RNA sequencing on thousands of individual cells isolated from spleen and blood. Unbiased transcriptional clustering revealed two distinct signatures differentiating between splenic and blood NK cells. This analysis at single-cell resolution identified three subpopulations in mouse spleen and four in human spleen, and two subsets each in mouse and human blood. A comparison of transcriptomic profiles within and between species highlighted the similarity of the two major subsets, NK1 and NK2, across organs and species. This unbiased approach provides insight into the biology of NK cells and establishes a rationale for the translation of mouse studies to human physiology and disease.
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•scRNA-seq on spleen and blood NK cells reveals organ-specific signatures•scRNA-seq reveals the heterogeneity of NK cells in the blood and spleen•scRNA-seq on NK cells defines NK1 as human CD56dim and mouse CD27−CD11b+ NK cells•scRNA-seq on NK cells defines NK2 as human CD56bright and mouse CD27+CD11b− NK cells
Several NK cell subsets have been reported in humans and mice, but their heterogeneity remains poorly characterized. Using high-throughput single-cell RNA-seq, Crinier et al. provide conserved tissue-specific gene signatures of NK cells from spleen and blood and identified two major NK cell subsets transcriptionally similar across organs and species.
Over the last decade, various new therapies have been developed to promote anti-tumor immunity. Despite interesting clinical results in hematological malignancies, the development of bispecific ...killer-cell-engager antibody formats directed against tumor cells and stimulating anti-tumor T cell immunity has proved challenging, mostly due to toxicity problems. We report here the generation of trifunctional natural killer (NK) cell engagers (NKCEs), targeting two activating receptors, NKp46 and CD16, on NK cells and a tumor antigen on cancer cells. Trifunctional NKCEs were more potent in vitro than clinical therapeutic antibodies targeting the same tumor antigen. They had similar in vivo pharmacokinetics to full IgG antibodies and no off-target effects and efficiently controlled tumor growth in mouse models of solid and invasive tumors. Trifunctional NKCEs thus constitute a new generation of molecules for fighting cancer.
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•NK cell engagers are multifunctional Abs targeting tumor antigens, NKp46 and CD16•NKCEs bring tumor cells and NK cells together and trigger tumor-cell destruction•NKCEs can show killing potency superior to therapeutic Abs in vitro and in vivo•NKCEs may improve benefit-risk profile for cancer treatment compared to BiTEs
Trifunctional antibodies that engage natural killer cells by binding NKp46 and CD16, in addition to an antigen on cancer cells, show higher potency than current clinically available therapeutic antibodies.
Immune checkpoint inhibitors have revolutionized cancer treatment. However, many cancers are resistant to ICIs, and the targeting of additional inhibitory signals is crucial for limiting tumor ...evasion. The production of adenosine via the sequential activity of CD39 and CD73 ectoenzymes participates to the generation of an immunosuppressive tumor microenvironment. In order to disrupt the adenosine pathway, we generated two antibodies, IPH5201 and IPH5301, targeting human membrane-associated and soluble forms of CD39 and CD73, respectively, and efficiently blocking the hydrolysis of immunogenic ATP into immunosuppressive adenosine. These antibodies promoted antitumor immunity by stimulating dendritic cells and macrophages and by restoring the activation of T cells isolated from cancer patients. In a human CD39 knockin mouse preclinical model, IPH5201 increased the anti-tumor activity of the ATP-inducing chemotherapeutic drug oxaliplatin. These results support the use of anti-CD39 and anti-CD73 monoclonal antibodies and their combination with immune checkpoint inhibitors and chemotherapies in cancer.
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•IPH5201 and IPH5301 block cell-borne and soluble CD39 and CD73, respectively•IPH5201 maintains immunogenic extracellular ATP•When used in combination with chemotherapy, IPH5201 promotes antitumor immunity•Targeting CD39 and CD73 synergistically promotes cancer patient T cell activation
The production of adenosine via CD39 and CD73 ectoenzymes participates in an immunosuppressive tumor microenvironment. Perrot et al. generated two antibodies, IPH5201 and IPH5301, targeting human CD39 and CD73, respectively. In vitro and in vivo data support the use of anti-CD39 and anti-CD73 mAbs in combination cancer therapies.
The innate lymphoid cell (ILC) family consists of natural killer (NK) cells, helper-like lymphoid cells (ILC1s, ILC2s, and ILC3s), and lymphoid tissue inducer (LTi) cells. Helper-like ILCs are ...considered the innate counterpart of T-helper cells because of similarities in their cytokine output and expression of key transcription factors. ILCs provide and regulate innate immune functions before the development of adaptive immunity. They are involved in host defense against pathogens, inflammation, tissue repair, and metabolic homeostasis. However, they can also be involved in inflammatory disorders and carcinogenesis. In this review, we summarize the latest research on ILC development and plasticity in humans and mice, focusing on the pathogenic role of helper-like ILCs in inflammatory disorders, such as asthma, Crohn’s disease (CD), and rheumatoid arthritis (RA).
ILCs comprise NK cells, helper-like ILCs (ILC1s, ILC2s, and ILC3s) and LTi cells. ILCs are involved in defense against viruses, parasites, and bacteria, and in tissue repair and metabolic processes.NK cells and helper-like ILCs are derived from a common ILC progenitor in both humans and mice.The identity of mature ILCs is not fixed, but is highly plastic and dependent on environmental signals.ILCs are also involved in inflammation, several inflammatory diseases, and cancer progression. Thus, ILCs might constitute novel putative therapeutic targets for different diseases.
Highlights ► Temporal orchestration of transcription factors for NK cell development. ► NK cell maturation depends on accessory cells. ► NK cell responsiveness is tuned by the environment. ► ...Intensity of inflammation dictates the antiviral and immunoregulatory outcome of NK cell activation.
Natural Killer (NK) cells are innate lymphoid cells (ILCs) capable of recognizing and directly killing tumor cells. They also secrete cytokines and chemokines, which participate in the shaping of the ...adaptive response. NK cells identify tumor cells and are activated through a net positive signal from inhibitory and activating receptors. Several activating NK cell receptors are coupled to adaptor molecules containing an immunoreceptor tyrosine-based activation motif (ITAM). These receptors include CD16 and the natural cytotoxic receptors NKp46, NKp44, NKp30 in humans. The powerful antitumor NK cell response triggered by these activating receptors has made them attractive targets for exploitation in immunotherapy. In this review, we will discuss the different activating receptors associated with ITAM-bearing cell surface receptors expressed on NK cells, their modulations in the tumor context and the various therapeutic tools developed to boost NK cell responses in cancer patients.
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