Combined anti-PD-1 and anti-CTLA-4 checkpoint blockade: Treatment of melanoma and immune mechanisms of action

Cytotoxic T-lymphocyte associated protein-4 (CTLA-4) and the Programmed Death Receptor 1 (PD-1) are immune checkpoint molecules that are well-established targets of antibody immunotherapies for the management of malignant melanoma. The monoclonal antibodies, Ipilimumab, Pembrolizumab, and Nivolumab, designed to interfere with T cell inhibitory signals to activate immune responses against tumors, were originally approved as monotherapy. Treatment with a combination of immune checkpoint inhibitors may improve outcomes compared to monotherapy in certain patient groups and these clinical benefits may be derived from unique immune mechanisms of action. However, treatment with checkpoint inhibitor combinations also present significant clinical challenges and increased rates of immune-related adverse events. In this review, we discuss the potential mechanisms attributed to single and combined checkpoint inhibitor immunotherapies and clinical experience with their use.     

自然杀伤细胞表面受体NKp30的研究进展

自然杀伤(NK)细胞无需预先致敏即可快速杀伤靶细胞,是机体发挥抗肿瘤免疫和抗感染免疫的重要执行者.NK细胞的活化与否取决于细胞表面活化性受体和抑制性受体信号的平衡.NKp30是NK细胞表面的一种重要的活化性受体,可接收相应配体如BAG-6、B7-H6等分子信号进而激活NK细胞,发挥抗肿瘤和抗感染免疫作用.同时NKp30也是肿瘤细胞和病原体发生免疫逃逸的重要靶点,可通过多种机制逃逸NK细胞杀伤.此外,NKp30还参与了NK细胞和树突状细胞(DCs)间的双向免疫调节.     

Chimeric antigen receptor- and natural killer cell receptor-engineered innate killer cells in cancer immunotherapy

Chimeric antigen receptor (CAR)-engineered T-cell (CAR-T) therapy has demonstrated impressive therapeutic efficacy against hematological malignancies, but multiple challenges have hindered its application, particularly for the eradication of solid tumors. Innate killer cells (IKCs), particularly NK cells, NKT cells, and γδ T cells, employ specific antigen-independent innate tumor recognition and cytotoxic mechanisms that simultaneously display high antitumor efficacy and prevent tumor escape caused by antigen loss or modulation. IKCs are associated with a low risk of developing GVHD, thus offering new opportunities for allogeneic “off-the-shelf” cellular therapeutic products. The unique innate features, wide tumor recognition range, and potent antitumor functions of IKCs make them potentially excellent candidates for cancer immunotherapy, particularly serving as platforms for CAR development. In this review, we first provide a brief summary of the challenges hampering CAR-T-cell therapy applications and then discuss the latest CAR-NK-cell research, covering the advantages, applications, and clinical translation of CAR- and NK-cell receptor (NKR)-engineered IKCs. Advances in synthetic biology and the development of novel genetic engineering techniques, such as gene-editing and cellular reprogramming, will enable the further optimization of IKC-based anticancer therapies.     

Immune checkpoint molecules in pregnancy: Focus on regulatory T cells

Regulatory T (Treg) cells are a specialized subpopulation of T cells that plays critical roles in the maintenance of immune homeostasis. Although efforts have been done, their role in human pregnancy is not fully understood. Numerous studies reported the presence of Treg cells throughout gestation by promoting maternal–fetal tolerance and fetal development. Furthermore, Treg population is heterogeneous as it is expressing different immune checkpoint molecules favoring immune suppressive function. Therefore, better understanding of the heterogeneity and function of Treg cells during pregnancy is critical for an effective immune intervention. Latest evidence has shown that several immune checkpoint molecules are closely associated with pregnancy outcome via multiple inhibitory mechanisms. Majority of these studies demonstrated the modulatory effects of immune checkpoint molecules on effector T-cell immunity, but their effects on Treg activation and function are still an enigma. In this review, we emphasize the potential influence of multiple immune checkpoint molecules, including CTLA-4, PD-1, Tim-3, LAG-3, and TIGIT, either in membrane or soluble form, on the function of decidual and peripheral Treg cells during pregnancy. Additionally, we discuss the promising future of targeting Treg cells via immune checkpoint molecules for pregnancy maintenance and prevention of complicated pregnancies.     

Interaction between natural killer cells and regulatory T cells: perspectives for immunotherapy

Regulatory T (Treg) cells and natural killer (NK) cells are key players in the immune system. The interaction between these two cell types has been reported to be beneficial in healthy conditions such as pregnancy. However, in the case of certain pathologies such as autoimmune diseases and cancer this interaction can become detrimental, as Treg cells have been described to suppress NK cells and in particular to impair NK cell effector functions. This review aims to discuss the recent information on the interaction between Treg cells and NK cells under healthy and pathologic conditions, to describe the specific conditions in which this interaction takes place, the effect of Treg cells on hematopoietic stem cell differentiation and the consequences of this interaction on the optimization of immunotherapeutic protocols.     

Targeted lysis of HIV-infected cells by natural killer cells armed and triggered by a recombinant immunoglobulin fusion protein: implications for immunotherapy

Natural killer (NK) cells play an important role in both innate and adaptive antiviral immune responses. The adaptive response typically requires that virus-specific antibodies decorate infected cells which then direct NK cell lysis through a CD16 mediated process termed antibody-dependent cellular cytotoxicity (ADCC). In this report, we employ a highly polymerized chimeric IgG1/IgA immunoglobulin (Ig) fusion protein that, by virtue of its capacity to extensively crosslink CD16, activates NK cells while directing the lysis of infected target cells. We employ HIV as a model system, and demonstrate that freshly isolated NK cells preloaded with an HIV gp120-specific chimeric IgG1/IgA fusion protein efficiently lyse HIV-infected target cells at picomolar concentrations. NK cells pre-armed in this manner retain the capacity to kill targets over an extended period of time. This strategy may have application to other disease states including various viral infections and cancers.     

Natural killer cells and malaria

Summary:  Malaria, caused by the infection with parasites of the germs Plasmodium , is one of the three most important infectious diseases worldwide, along with tuberculosis and infection with human immunodeficiency virus. Natural killer (NK) cells are lymphocytes classically involved in the early defense against viral infections and intracytoplasmic bacterial infections and are also implicated during the course of tumor development and allogeneic transplantation. These cells display important cytotoxic activity and produce high levels of proinflammatory cytokines. In both mouse and human models of malaria, NK cells appear to be a major source of interferon-γ during the early phase of infection. In humans, indirect signaling through monocytes/macrophages required to optimally stimulate NK cell activity. However, the in vivo functions of NK cells during malaria are still enigmatic, and many issues remain to be dissected, such as the molecular basis of the direct recognition of iRBCs by NK cells.     

Natural killer cells in viral infection: more than just killers

Summary:  Innate immunity was believed originally to serve simply as the first-line defense against infection and malignancy, with adaptive immunity imposing specificity and ensuring that appropriate responses are mounted against chronic or reoccurring challenges. In this model of immunity, innate and adaptive immune responses are sequential, essentially non-overlapping, and interactions between components of each response limited or non-existent. Over the last 5 years, it has become increasingly evident that interactions between elements of the innate and adaptive immune systems are common. Indeed, it is now clear that the generation and maintenance of effective immunity require an extensive array of interactions between multiple components of the immune system. This review discusses recent advances in this area with particular emphasis on the role of natural killer cells in shaping the adaptive immune response to viral infection.     

The unique profile of cord blood natural killer cells balances incomplete maturation and effective killing function upon activation

Cord blood (CB) is increasingly used as a source of stem cells for hematopoietic stem cell transplantation, and natural killer (NK) cells may be the effectors of the antileukemic response observed after CB transplantation. Here, we analyzed the phenotype and functions of CB NK cell subsets. We determined that the percentage of NK cells was higher in CB compared with peripheral blood (PB). Furthermore, there was a higher percentage of the CD56(bright) subset in CB. CB NK cells reached a late stage of differentiation, but exhibited higher expression of NKG2A and expressed fewer killer-cell immunoglobulin-like receptors, suggesting an incomplete maturation. CB NK cells highly expressed CXCR4, but did not express L-selectin, highlighting unique homing properties of CB NK cells. CB NK cells proliferated in response to interleukin-2 and degranulated in response to stimulation with tumor cells, but failed to lyse K562 cells in (51)Cr-release assay. CB NK cells exhibited a lower interferon-γ production in comparison with PB NK cells. Culture with IL-2 increased CB NK cell functions. Our study sheds light on CB NK cell properties and highlights the potential of CB as a source of NK cells for immunotherapy.     

调节性T细胞相关负性分子与感染免疫

调节性T细胞通过免疫抑制与免疫耐受机制影响疾病的发展。与调节性T细胞相关的CTLA-4、PD-1等负性分子在调节性T细胞的调节功能中起重要作用。本文拟对CTLA-4、PD-1和调节性T细胞的关系以及在病毒感染、细菌感染、寄生虫感染等免疫病中的调节机制作一综述。     

Natural killer cell receptor expression reflects the role of human cytomegalovirus in the pathogenesis of a subset of CD4+ T-cell large granular lymphocytosis

A high frequency of CD4(+) T-cell large granular lymphocyte (T-LGL) lymphocytosis occurs in human leukocyte antigen (HLA) -DRB1*0701 individuals displaying monoclonal expansions of Vβ13.1+ CD4(+) T-cell clones, which specifically respond to human cytomegalovirus (HCMV) antigens. We previously reported the expression of natural killer (NK)-cell associated receptors (NKR) by HCMV-specific cytolytic CD4(+) T cells from healthy donors. In the present study a high expression of different NKR (i.e., NKG2D, killer Ig-like receptors (KIR), CD94, ILT2) was observed in CD4(+) T cells from both Vβ13.1- and Vβ13.1+ CD4(+) T-LGL cases. Remarkably, elevated numbers of CD94/NKG2C+ NK cells, previously shown to expand in association to HCMV infection, were preferentially found in Vβ13.1+ T-LGL, further supporting its role in the pathogenesis of a subset of CD4(+) T-LGL.     

Natural killer cell receptors and their ligands in liver diseases

The liver is a distinctive immune organ with predominant innate immunity, being rich in innate immune cells such as natural killer (NK) cells. In humans, NK cells comprise about 30%–50% of intrahepatic lymphocytes, whereas peripheral blood lymphocytes contain about 5%–20% NK cells. Accumulating evidence suggests that NK cells play an important role not only in host defense against invading microorganisms and tumor transformation in the liver but also in liver injury and repair. In recent years, significant progress has been made in terms of understanding how NK cells recognize their target cells and carry out their effector functions. It is now clear that NK cells are strictly regulated by numerous activating and inhibitory NK cell receptors that recognize various classes of cell surface ligands, some of which are expressed by normal healthy cells. Therefore, to further elucidate the involvement of NK cells in the pathogenesis of liver diseases, an understanding of recent advances in NK cell biology is crucial. This review provides an overview of recent advances in our knowledge of human NK cell receptors and their ligands in the context of liver diseases.     

Early appearance and activation of natural killer cells in tumor-infiltrating lymphoid cells during tumor development

We investigated NK cell infiltration into tumor developing lesions at early stage of tumor development after intraperitoneal inoculation of 3LL lung carcinoma into syngeneic C57BL/6 mice. Natural killer (NK) cells, which were detected by anti-NK 1.1 monoclonal antibody (mAb), remarkably increased in number in tumor-developing lesions (peritoneal cavity) as early as day 3 after inoculation of 3LL. The tumor-infiltrating NK cells from 3LL-inoculated mice produced a high level of interferon-γ by co-culture with 3LL and showed enhanced cytotoxic activities against both NK-sensitive (YAC-1) and NK-resistant (3LL and P815) tumors. Furthermore, mice depleted of NK cells by injection of anti-NK 1.1 mAb or antiasialo GM1 antibody showed shorter survival times after intraperitoneal inoculation of 3LL when compared with control mice. These results suggest that NK cells infiltrate the tumor-developing lesion at an early stage and may participate in the early protection against tumors through production of a high amount of interferon-γ and enhanced cytotoxicity at tumor-bearing sites.     

Natural killer T cells contribute to airway eosinophilic inflammation induced by ragweed through enhanced IL-4 and eotaxin production

Although NKT cells have been found to be capable of modulating immune responses in several model systems, the role of NKT cells in allergy remains unclear. Using CD1 gene knockout (KO) mice, which lack NKT cells, we examined the function of NKT cells in the development of allergic inflammation induced by a common airborne human allergen, ragweed. The data showed that airway eosinophilia and mucus overproduction induced by ragweed were significantly reduced in CD1 KO mice, which was correlated with significantly lower allergen-driven IL-4 production and lower eotaxin responses in the airways of CD1 KO mice. Moreover, both ragweed-specific and total serum IgE levels in CD1 KO mice were significantly lower than those in control BALB/c mice. The reduced allergic reaction in CD1 KO mice is not due to intrinsic deficiency because they showed normal levels of immune cells and function. In addition, in vivo stimulation of NKT cells using their natural ligand, alpha-galactosylceramide, enhanced ragweed-induced airway eosinophilia, IL-4, and eotaxin production in control, but not CD1 KO mice. These data provide in vivo evidence for the involvement of NKT cells in the allergic mechanisms responsible for allergen-driven cytokine and chemokine production and airway inflammation.     

Natural killer cells in patients with pulmonary tuberculosis

Laboratory of Clinical Immunology, Central Research Institute of Tuberculosis, Ministry of Health of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR A. G. Khomenko.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 112, No. 7, pp. 76–78, July, 1991.     

HIV感染症状长期不进展者NK细胞变化研究

目的探讨HIV长期不进展者NK细胞的变化. 方法应用流式细胞术对HIV长期不进展者、典型进展者和HIV-抗体阴性正常对照外周血NK细胞、NKT细胞及NK细胞趋化因子受体等进行研究. 结果长期不进展者NKT细胞绝对计数与正常对照差异无统计学意义(P＝0.301),高于HIV感染者和艾滋病病人(P＝0.01, P＝0.002);长期不进展者NK细胞绝对计数低于正常对照(P＝0.03),高于HIV感染者和艾滋病病人(P＝0.005, P＜0.0001);长期不进展者NK细胞与CD4+ T淋巴细胞呈正相关(r＝0.393,P＝0.001);NKT细胞与CD8+ T淋巴细胞呈正相关(r＝0.372,P＝0.002).长期不进展者NK细胞表达的CCR5受体低于典型进展者和正常对照(P＜0.01). 结论 NK细胞的变化与HIV疾病进展相关,值得深入研究.