Novel Association of Killer Cell Immunoglobulin-like Receptor Genes with EBV-infectious Diseases in Children

Killer cell immunoglobulin-like receptors （KIRs） which are mainly expressed on natural killer （NK） cells are implicated in many virus infections. However, it is unclear whether or not KIRs are associated with susceptibility to Epstein-Barr virus （EBV） infection related diseases. Therefore, the purpose of our study was to investigate possible correlation between polymorphisms of KIR genes and infectious mononucleosis （IM）/EBV-associated hemophagocytic Iymphohistiocytosis （EBV-HLH）. The polymorphisms of KIR genes were detected by polymerase chain reaction with sequence-specific primers （PCR-SSP）. The results would contribute to clarify the association of KIRs with EBV induced diseases, and provide new insights into the role of NK cells and innate immune response against viral infections and/or subsequent progression.

Advancement of chimeric antigen receptor-natural killer cells targeting hepatocellular carcinoma

With the advance of genome engineering technology,chimeric antigen receptors(CARs)-based immunotherapy has become an emerging therapeutic strategy for tumors.Although initially designed for T cells in tumor immunotherapy,CARs have been exploited to modify the function of natural killer(NK)cells against a variety of tumors,including hepatocellular carcinoma(HCC).CAR-NK cells have the potential to sufficiently kill tumor antigen-expressing HCC cells,independent of major histocompatibility complex matching or prior priming.In this review,we summarize the recent advances in genetic engineering of CAR-NK cells against HCC and discuss the current challenges and prospects of CAR-NK cells as a revolutionary cellular immunotherapy against HCC.

Transient Receptor Potential Melastatin 3 and Intracellular Calcium in Natural Killer Cells in Multiple Sclerosis

Background: Natural killer (NK) cell phenotypes have reported to be implicated in the pathomechanism of Multiple Sclerosis (MS). Several investigators have observed reduced peripheral numbers, reduced cytotoxic activity, and altered CD56Dim and CD56Bright NK cell phenotypes. This current project, for the first time, investigates the NK cell cytotoxicity, calcium mobilisation and transient receptor potential melastatin 3 (TRPM3) surface expression. Methods: NK cell cytotoxic activity and calcium signaling were examined in CD56Dim and CD56Bright NK cells before and after stimulation using Ionomycin, Pregnenolone sulphate, 2-Aminoethoxydiphenyl borate and Thapsigargin. Purified NK cells were labelled with antibodies to determine TRPM3, CD69 and CD107a surface expression using flow cytometry. Results: Twenty-two MS patients and 22 healthy controls were recruited for this project. Twelve of the 22 previously received Alemtuzumab (Lemtrada®) and the remaining ten reported nil medication. We report TRPM3 was significantly increased in untreated MS patients compared with healthy controls and treated MS patients (p-value 0.034). There was a significant decrease in CD69 surface expression on CD56Dim NK cell phenotype for untreated MS patients (p-value 0.031) and treated MS patients (p-value 0.036). We report altered calcium mobilisation in CD56Bright NK cells and to a lesser extent CD56Dim NK cells between healthy controls, treated and untreated MS patients. Conclusion: This investigation suggests variations in TRPM3 expression and calcium mobilisation of NK cells may be implicated in the pathogenesis of MS. Further investigation is required to determine the mechanism by which alemtuzumab alters calcium signaling in NK cells.

Natural Killer Cell-Based Immunotherapy for Cancer: Advances and Prospects

Natural killer (NK) cells are key innate immune cells that provide the first line of defense against viral infection and cancer. Although NK cells can discriminate between "self" and "non-self," recognize abnormal cells, and eliminate transformed cells and malignancies in real time, tumors develop several strategies to escape from NK cell attack. These strategies include upregulating ligands for the inhibitory receptors of NK cells and producing soluble molecules or immunosuppressive factors. Various types of NK cells are currently being applied in clinical trials, including autologous or allogeneic NK cells, umbilical cord blood (UCB) or induced pluripotent stem cell (iPSC)-derived NK cells, memory-like NK cells, and NK cell line NK-92 cells, for the treatment of different types of tumors. Chimeric antigen receptors (CARs)-NK cells have recently shown great potential due to their redirect specificity and effective antitumor activity. In this review, we summarize the mechanisms of tumor escape from NK cell recognition, the current status and advanced progress of NK cell-based immunotherapy, ways of enhancing the antitumor capacity of NK cells in vivo, and major challenges for clinical practice in this field.

Potential role of killer immunoglobulin receptor genes among individuals vaccinated against hepatitis B virus in Lebanon

AIMTo explore the role of killer immunoglobulin receptor (KIR) genes in responsiveness or non-responsiveness to vaccination against hepatitis B virus. METHODSWe recruited 101 voluntary participants between March 2010 and December 2011. Sera samples from vaccinated and non-vaccinated participants were tested for the presence of anti-HBs antibodies as a measure of protection against hepatitis B, hepatitis B surface antigen and hepatitis B core antibody as indicators of infection by enzyme-linked immunosorbent assay. KIR gene frequencies were determined by polymerase chain reaction. RESULTSSera samples from 99 participants were tested for the levels of anti-HBs as an indicator of protection (≥ 10 mIU/mL) following vaccination as defined by the World Health Organization international reference standard. Among the vaccinated participants, 47% (35/74) had anti-HBs titers above 100 mIU/mL, 22% (16/74) had anti-HBs ranging between 10-100 mIU/mL, and 20% (15/74) had values of less than 10 mIU/mL. We report the lack of significant association between the number of vaccine dosages and the titer of antibodies among our vaccinated participants. The inhibitory KIR2DL1, KIR2DL4, KIR3DL1, KIR3DL2, and KIR3DL were detected in more than 95%, whereas KIR2DL2, KIR2DL3, KIR2DL5 (KR2DL5A and KIR2DL5B) were expressed in 56%, 84% and 42% (25% and 29%) of participants, respectively. The observed frequency of the activating KIR genes ranged between 35% and 55% except for KIR2DS4, detected in 95% of the study participants (40.6% 2DS4*001/002; 82.2% 2DS4*003/007). KIR2DP1 pseudogene was detected in 99% of our participants, whereas KIR3DP*001/02/04 and KIR3DP1*003 had frequencies of 17% and 100%, respectively. No association between the frequency of KIR genes and anti-HBs antibodies was detected. When we compared the frequency of KIR genes between vaccinated individuals with protective antibodies titers and those who lost their protective antibody levels, we did not detect a significant difference. KIR2DL5B was significantly different among different groups of vaccinated participants (group I > 100 mIU/mL, group II 10-100 mIU/mL, group III CONCLUSIONTo our knowledge, this is the first study screening for the possible role of KIR genes among individuals vaccinated against hepatitis B virus (HBV). Our results can be used to design larger studies to better understand the role of KIR genes in protection against or susceptibility to HBV post vaccination.

Targeted Therapy of CEA-CAR-NK Cells Against Colorectal Cancer Cells

Objective:Investigate the cytotoxic effect of CAR-NK cells targeting CEA on colorectal cancer cells with positive CEA expression.Methods:The mRNA and protein levels of CEA in different CRC cell lines were detected by qRT-PCR and Western blot analysis.Lentiviral transduction was used to construct CAR-NK cells and empty vector CON-NK cells targeting CEA.Fluorescence microscopy and WB were used to determine whether the cells successfully constructed and expressed CAR structures.The effector NK cells were co-cultured with target cells,and the levels of LDH,IFN-γ,and GM-CSF were detected.The killing rate of effector cells was calculated,and the release of cytokines during the killing of target cells by different effector cells was compared.Results:The expression level of CEA in colorectal cancer patients was significantly higher than that in normal samples and other tumor samples,and the prognosis survival time of patients with high CEA expression was lower than that of CRC patients with low or no CEA expression(P<0.05).The CEA expression of the HT29 cell line was significantly higher than that of the SW1116 cell line at both the mRNA and protein levels.CEA-CAR-NK92 cells and CON-NK92 cells expressed green fluorescence under a microscope,and WB results showed that CEA-CAR-NK92 cells successfully expressed the CAR structure.Compared with CON-NK92 cells and NK92 cells,CEA-CAR-NK92 cells effectively killed HT29 cells(P<0.05).CEA-CAR-NK92 cells secreted a large amount of IFN-γand GM-CSF during the killing of HT29 cells,while the cytokine secretion of CON-NK92 cells and NK92 cells was not significant(P<0.05).Conclusion:CAR-NK92 cells targeting CEA can effectively kill CEA-positive colorectal cancer cells.

Emergence of immunotherapy as a novel way to treat hepatocellular carcinoma

Tumor immunity proceeds through multiple processes, which consist of antigen presentation by antigen presenting cells(APCs) to educate effector cells and destruction by the effector cytotoxic cells. However, tumor immunity is frequently repressed at tumor sites. Malignantly transformed cells rarely survive the attack by the immune system, but cells that do survive change their phenotypes to reduce their immunogenicity. The resultant cells evade the attack by the immune system and form clinically discernible tumors. Tumor microenvironments simultaneously contain a wide variety of immune suppressive molecules and cells to dampen tumor immunity. Moreover, the liver microenvironment exhibits immune tolerance to reduce aberrant immune responses to massively-exposed antigens via the portal vein, and immune dysfunction is frequently associated with liver cirrhosis, which is widespread in hepatocellular carcinoma(HCC) patients. Immune therapy aims to reduce tumor burden, but it is also expected to prevent non-cancerous liver lesions from progressing to HCC, because HCC develops or recurs from noncancerous liver lesions with chronic inflammatory states and/or cirrhosis and these lesions cannot be cured and/or eradicated by local and/or systemic therapies. Nevertheless, cancer immune therapy should augment specific tumor immunity by using two distinct measures: enhancing the effector cell functions such as antigen presentation capacity of APCs and tumor cell killing capacity of cytotoxic cells, and reactivating the immune system in immune-suppressive tumor microenvironments. Here, we will summarize the current status and discuss the future perspective on immune therapy for HCC.

Hepatitis B virus-persistent infection and innate immunity defect: Cell-related or virus-related?

The outcomes of hepatitis B virus(HBV) infection are closely related to the age at which infection was acquired. Infection acquired in adult life tends to be selflimited, in contrast to perinatal acquirement, for which chronic persistence of the HBV is a general outcome. Innate immunity plays an indispensable role in early virus infection, facilitating virus clearance. However, it has been reported that HBV is under-recognized and poorly eliminated by the innate immune system in the early stages of infection, possibly explaining the long-lasting persistence of viremia afterwards. Furthermore, due to the existence of covalently closed circular DNA, chronic HBV clearance is very difficult, even when patients are given interferon-α and nucleotide/nucleoside analogs for antiviral therapy. The mechanism by which HBV evades innate immune recognition and establishes persistent infection remains a subject of debate. Besides, some researchers are becoming more interested in how to eradicate chronic HBV infection by restoring or boosting innate immunity. This review aimed to summarize the current knowledge on how intrahepatocyte signaling pathways and innate immune cells act after the onset of HBV infection and how these actions are related to the persistence of HBV. We anticipate the insights presented herein to be helpful for future development of novel immune therapeutic strategies to fight HBV infection.

Evaluation of antibody-dependent cell-mediatedcy totoxicity activity and cetuximab response in KRAS wildtype metastatic colorectal cancer patients

AIM:To investigate the prognostic role of invariant natural killer T(iNKT) cells and antibody-dependent cell-mediated cytotoxicity(ADCC) in wild type KRAS metastatic colorectal cancer(mC RC) patients treated with cetuximab.METHODS: Forty-one KRAS wt mC RC patients,treated with cetuximab and irinotecan-based chemotherapy in Ⅱ and Ⅲ lines were analyzed. Genotyping of single nucleotide polymorphism(SNP)s in the FCGR2A,FCGR3A and in the 3' untranslated regions of KRAS and mutational analysis for KRAS,BRAF and NRAS genes was determined either by sequencing or allelic discrimination assays. Enriched NK cells were obtained from lymphoprepperipheral blood mononuclear cell and iN KT cells were defined by co-expression of CD3,TCRVα24,TCRVβ11. ADCC was evaluated as ex vivo NK-dependent activity,measuring lactate dehydrogenase release.RESULTS: At basal,mCRC patients performing ADCC activity above the median level(71%) showed an improved overall survival(OS) compared to patients with ADCC below(median 16 vs 8 mo;P=0.026). We did not find any significant correlation of iN KT cells with OS(P=0.19),albeit we observed a trend to a longer survival after 10 mo in patients with iN KT above median basal level(0.382 cells/microliter). Correlation of OS and progression-free survival(PFS) with interesting SNPs involved in ADCC ability revealed not to be significant. Patients carrying alleles both with A in FCGR2 A and TT in FCGR3A presented a trend of longer PFS(median 9 vs 5 mo;P=0.064). Chemotherapy impacted both iN KT cells and ADCC activity. Their prognostic values get lost when we analysed them after 2 and 4 mo of treatment.CONCLUSION: Our results suggest a link between iN KT cells,basal ADCC activity,genotypes in FCGR2A and FCGR3A,and efficacy of cetuximab in KRAS wt mC RC patients.

Multiple sclerosis and the role of immune cells

Multiple sclerosis(MS) is a complex disease with many different immune cells involved in its pathogenesis, and in particular T cells as the most recognized cell type. Recently, the innate immune system has also been researched for its effect on the disease. Hence, cells of the immune system play vital roles in either ameliorating or exacerbating the disease. The genetic and environmental factors, as well as the etiology and pathogenesis are of utmost importance for the development of MS. An insight into the roles play by T cells, B cells, natural killer cells, and dendritic cells in MS and the animal model experimental autoimmune encephalomyelitis, will be presented. Understanding the mechanisms of action for current therapeutic modalities should help developing new therapeutic tools to treat this disease and other autoimmune diseases.

Peripheral blood NKT cell number and function in patients with Graves disease and their correlation with hyperthyroidism

Objective:To assess the peripheral blood NKT cell number and function in patients with Graves disease and study their correlation with hyperthyroidism.Methods: The patients who were diagnosed with Graves disease in our hospital between May 2014 and September 2016 were selected as GD group, and 55 healthy volunteers who received physical examination in our hospital during the same period were selected as control group. Peripheral blood was collected to determine the number of CD3+CD56+NKT cells, and serum was collected to detect the contents of cytokines and thyroid function indexes.Results: Peripheral blood CD3+CD56+NKT cell number in Graves disease group was significantly lower than that in control group;serum IL-2, IFN-γ, TNF-α, IL-10 and TGF-β contents in GD group were significantly lower than those in control group and positively correlated with peripheral blood CD3+CD56+NKT cell number while IL-4, IL-5, IL-17, FT3, FT4, TPOAb, TgAb and TRAb contents were significantly higher than those in control group and negatively correlated with peripheral blood CD3+CD56+NKT cell number.Conclusion:The abnormal reduction of peripheral blood NKT cell number in patients with Graves disease can affect the balance of Th1/Th2 and Th17/Treg and increase the TRAb secretion to cause hyperthyroidism.

莫诺苯宗对肺腺癌细胞自噬和凋亡的分子机制研究

目的:探究莫诺苯宗和自然杀伤细胞激活受体基因(KLRC3)对肺腺癌(LUAD)细胞凋亡和自噬的影响,为LUAD的治疗提供理论基础。方法:分别使用不同浓度莫诺苯宗处理LUAD细胞,并采用CCK-8法检测莫诺苯宗对LUAD细胞活力的影响;随后,使用80μmol/L的莫诺苯宗、50 nmol/L的KLRC3干扰质粒(si-KLRC3)、和100 nmol/L自噬抑制剂3-甲基腺嘌呤(3-MA)1.5μg/ml KLRC3过表达载体(pcDNA-KLRC3)处理细胞后采用流式细胞术和Western blotting检测细胞凋亡以及凋亡相关蛋白和自噬相关蛋白的表达量。结果:莫诺苯宗浓度大于20μmol/L时可有效减弱LUAD细胞活力,且以剂量依赖性地促进了LUAD细胞的凋亡和自噬(均P<0.05)。KLRC3在LUAD细胞中低表达,干扰KLRC3减弱了莫诺苯宗对LUAD细胞自噬和凋亡的促进作用,比较差异有统计学意义(均P<0.05)。此外,过表达KLRC3也促进了LUAD细胞的凋亡和自噬,而KLRC3和莫诺苯宗对LUAD细胞凋亡和自噬的促进作用均可被3-MA所抵消,比较差异有统计学意义(均P<0.05)。结论:莫诺苯宗可能通过促进KLRC3的表达诱导自噬进而促进LUAD细胞的凋亡。

肝细胞癌过继细胞疗法研究进展

肝细胞癌是严重威胁人类生存的一类疾病,中国肝细胞癌死亡率居世界第三。由于肝细胞癌发病早期无特异性症状,晚期的治疗方案又存在复发率高等的种种弊端,因此寻找行之有效的治疗新方法迫在眉睫。过继细胞疗法是一种细胞免疫疗法,在肝脏多样化和复杂的免疫微环境中,通过结合肿瘤特异性抗原或是非特异性的调节免疫平衡,过继细胞疗法在肝细胞癌的治疗中逐渐发挥出优势。在这篇综述中我们阐述了肝细胞癌靶向治疗常用生物标志物的形态结构及信号通路,探讨总结了近年来过继细胞疗法治疗肝细胞癌的研究手段及取得的临床效果,并对接下来的研究方向进行了展望。

吉林地区朝、满、汉3个民族KIR基因的分布频率研究

目的通过分析吉林地区汉族、满族及朝鲜族的杀伤细胞免疫球蛋白样受体(KIR)基因的频率与多态性,为探究KIR基因与疾病关联提供基础数据支持。方法采用聚合酶链反应-序列特异性引物(PCR-SSP)技术对吉林地区129名满族、198名朝鲜族及201名汉族人群的KIR基因进行分型。结果KIR3DL2、KIR3DL3、KIR3DP1及KIR2DL4在所有检测对象中均为100%检出。KIR2DL1、KIR2DL3、KIR2DS4、KIR3DL1及KIR2DP1等基因在这3个民族中的检出频率较高,介于93%~98%之间。相比之下,KIR2DL2、KIR2DL5、KIR3DS1、KIR2DS1、KIR2DS2、KIR2DS3及KIR2DS5的检出率较低,分布在13%~45%。特别是满族KIR2DL5(17.83%)与KIR2DS1(17.83%)的基因检出频率显著低于吉林地区朝鲜族(42.93%、47.47%)和汉族(33.83%、33.33%);吉林地区朝鲜族KIR2DL5(42.93%)与KIR2DS1(47.47%)的检出频率显著高于汉族(33.83%、33.33%)和满族(17.83%、17.83%);吉林地区汉族单体型KIRAA的频率在吉林3个受检民族中是最高的为61.19%,显著高于朝鲜族(42.93%),以上各组差异比较P<0.05,经Bonferroni校正后,Pc<0.05。结论吉林地区的朝鲜族、满族与汉族在KIR基因分布方面既体现了中国人群KIR基因多态性,又各自展示了独特的民族遗传特性和地域性。

嵌合抗原受体T细胞免疫疗法在晚期胃癌中的应用进展

胃癌是最常见的恶性肿瘤之一,当前我国胃癌就诊患者仍以进展期为主,晚期患者就诊时多已失去手术治疗的机会,而传统的放疗、化疗和靶向治疗效果并不理想。嵌合抗原受体(CAR)-T细胞(CAR-T)免疫疗法作为一种新的治疗手段,在血液系统恶性肿瘤中疗效显著,也为胃癌的免疫治疗开辟了新途径。然而,由于胃癌的异质性、肿瘤微环境免疫抑制、肿瘤靶抗原逃逸及脱靶毒性等问题,使得CAR-T免疫疗法在胃癌治疗中的应用存在挑战。本文综述了CAR的结构及CAR-T治疗原理、CAR-T治疗晚期胃癌的主要靶点及治疗现状,并探讨了CAR-T治疗胃癌面临的挑战,旨在为晚期胃癌的临床免疫治疗提供新思路。

黄芪含药血清对NK细胞活性、NKG2A、NKG2D及细胞因子IFN-γ表达的影响

目的探讨黄芪含药血清对自然杀伤(NK)细胞的杀伤活性和NKG2D、NKG2A、细胞因子干扰素-γ(IFN-γ)表达水平的影响。方法20只SPF级SD大鼠,随机分成黄芪低、中、高剂量组(3.1、6.2、12.4 g/kg体重)和正常对照组,灌胃后制备含药血清。用NK细胞专用培养基培养NK-92MI细胞,用1640培养基培养YAC-1细胞。将NK-92MI细胞与20%不同剂量黄芪含药血清及正常对照血清孵育48 h,即分别为正常对照组、黄芪低剂量组、黄芪中剂量组以及黄芪高剂量组。通过乳酸脱氢酶(LDH)释放测定方法检测NK细胞对靶细胞YAC-1的杀伤活性,ELISA法检测IFN-γ的水平,Western blot检测NKG2D以及NKG2A蛋白表达水平。结果与正常对照组和黄芪低剂量组相比,黄芪中、高剂量组的NK细胞活性显著升高(P<0.01)。IFN-γ的表达在黄芪低、中、高剂量组中均升高,但不随浓度升高而增强。与正常对照组相比,黄芪低、中剂量组NKG2D蛋白表达水平明显升高(P<0.01),而NKG2A蛋白表达水平在各组间无明显差异(P>0.05)。结论黄芪含药血清可增强NK细胞杀伤活性、上调IFN-γ表达水平、上调NK细胞活化型受体的表达,通过调控NK细胞实现对机体的保护作用。

Revolutionizing gastric cancer treatment:The potential of immunotherapy

Gastric cancer,a prevalent malignancy worldwide,ranks sixth in terms of frequency and third in fatality,causing over a million new cases and 769000 annual deaths.Predominant in Eastern Europe and Eastern Asia,risk factors include family medical history,dietary habits,tobacco use,Helicobacter pylori,and Epstein-Barr virus infections.Unfortunately,gastric cancer is often diagnosed at an advanced stage,leading to a grim prognosis,with a 5-year overall survival rate below 5%.Surgical intervention,particularly with D2 Lymphadenectomy,is the mainstay for early-stage cases but offers limited success.For advanced cases,the National Comprehensive Cancer Network recommends chemotherapy,radiation,and targeted therapy.Emerging immunotherapy presents promise,especially for unresectable or metastatic cases,with strategies like immune checkpoint inhibitors,tumor vaccines,adoptive immunotherapy,and nonspecific immunomodulators.In this Editorial,with regards to the article“Advances and key focus areas in gastric cancer immunotherapy:A comprehensive scientometric and clinical trial review”,we address the advances in the field of immunotherapy in gastric cancer and its future prospects.

胃癌淋巴细胞亚群中KLRG1和TIGIT的表达及意义

目的探讨胃癌患者外周血、癌及癌旁组织淋巴细胞中CD4^(+)T、CD8^(+)T、NK及NKT细胞上杀伤细胞凝集素样受体G1(Killer cell lectin-like receptor G1,KLRG1)、T细胞免疫球蛋白和ITIM结构域蛋白(T cell immunoglobulin and ITIM domains,TIGIT)的表达水平差异,并探讨其与临床特征、预后及免疫疗效的关系。方法纳入2022年1月-2023年12月新疆医科大学附属肿瘤医院行手术的初治胃癌患者,留取癌组织36例,癌旁组织31例,采集15例患者治疗前的外周血,通过流式细胞术检测外周血、癌和癌旁组织淋巴细胞中CD4^(+)T、CD8^(+)T、NK及NKT细胞上KLRG1和TIGIT的表达,并分析其表达与临床特征的关系;利用Kaplan-Meier Plotter在线数据库分析KLRG1和TIGTI在胃癌中的预后价值;从TCIA数据库中获得免疫表型分数(IPS)探讨KLRG1和TIGIT表达对免疫治疗的敏感性。结果(1)在GC癌组织中KLRG1^(+)CD8^(+)T细胞、KLRG1^(+)NKT细胞、TIGIT^(+)CD8^(+)T细胞、TIGIT^(+)CD4^(+)T细胞、TIGIT^(+)NKT、TIGIT^(+)NK、KLRG1^(+)TIGIT^(+)CD8^(+)T细胞、KLRG1^(+)TIGIT^(+)CD4^(+)T细胞表达高于癌旁组织,差异均具有统计学意义(P<0.05)。(2)在外周血中KLRG1^(+)CD8^(+)T细胞、KLRG1^(+)NKT细胞表达高于癌组织,差异均具有统计学意义(P<0.05),而TIGIT^(+)CD4^(+)T细胞、TIGIT^(+)CD8^(+)T细胞外周血中的表达低于癌组织,差异均具有统计学意义(P<0.05)。(3)KLRG1^(+)CD4^(+)T细胞、KLRG1^(+)CD8^(+)T细胞、KLRG1^(+)NKT细胞与肿瘤指标CA199呈正相关(r分别为0.37、0.45、0.40,P<0.05),KLRG1^(+)NKT细胞与CA125呈正相关(r=0.33,P<0.05)。(4)KLRG1高表达组患者的中位总生存时间、中位首次进展生存时间、中位进展后生存时间均短于KLRG1低表达组,差异均有统计学意义(P<0.05)。(5)在预测免疫治疗疗效方面,KLRG1和TIGIT高表达组对抗PD-1治疗以及抗PD-1和抗CTLA4联合治疗的反应优于低表达组(P<0.001)。结论KLRG1和TIGIT在胃癌组织中高表达,且KLRG高表达与胃癌的不良预后有关,KLRG1和TIGIT的表达可能有助于预测胃癌患者免疫治疗疗效。

通用型CAR-NK细胞治疗系统性红斑狼疮的应用与展望

系统性红斑狼疮(SLE)的特点是B细胞异常活化产生大量自身抗体,这些自身抗体与自身抗原形成免疫复合物诱发系统性炎症,导致全身多系统多器官受累。现有靶向B细胞治疗策略(如贝利尤单抗、泰它西普及利妥昔单抗等)的临床疗效仍然有限,近年来靶向CD19的嵌合抗原受体(CAR)-T细胞治疗SLE展现出卓越的疗效。但自体CAR-T细胞治疗存在细胞因子释放综合征、T细胞肿瘤、感染等潜在风险,且价格昂贵。CAR-自然杀伤(NK)细胞治疗是现货型细胞疗法,其安全性高,无神经毒性及肿瘤化风险,且治疗费用低。目前,CAR-NK细胞在治疗血液系统肿瘤中取得了显著的研究成果,且CAR-NK细胞治疗SLE的初步临床研究展现出良好的治疗效果、优异的安全性及可预期的持久性。本文将重点阐述新一代通用型CAR-NK细胞的特点及其用于治疗复发难治性SLE的最新临床研究结果,展望其治疗SLE及B细胞相关自身免疫病的广阔前景。

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,andγδT 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.