Immune evasion and therapeutic opportunities based on natural killer cells

Natural killer(NK)cells can elicit an immune response against malignantly transformed cells without recognizing antigens,and they also exhibit cytotoxic effects and immune surveillance functions in tumor immunotherapy.Although several studies have shown the promising antitumor effects of NK cells in immunotherapy,their function is often limited in the tumor microenvironment because tumor cells can easily escape NK cell-induced death.Thus,for efficient tumor immunotherapy,the mechanism by which tumor cells escape NK cell-induced cytotoxicity must be fully understood.Various novel molecules and checkpoint receptors that mediate the disruption of NK cells in the tumor microenvironment have been discovered.In this review,we analyze and detail the major activating and inhibitory receptors on the surface of NK cells to delineate the mechanism by which tumor cells suppress NKG2D ligand expression and increase tumor receptor and inhibitory receptor expression[NKG2A,programmed cell death1(PD-1),and T-cell immunoglobulin and immunoreceptor tyrosine inhibitory motif(TIGIT)]on the NK cell surface,and thus inhibit NK cell activity.We also reviewed the current status of treatments based on these surface molecules.By comparing the therapeutic effects related to the treatment status and bypass mechanisms,we attempt to identify optimal single or combined treatments to suggest new treatment strategies for tumor immunotherapy.

Natural killer cells in tumor immunotherapy

Cancer is the second most common cause of death worldwide and remains one of the critical public health problems of our time1.Recently,immunotherapy has considerably improved the outcomes of patients with advanced cancers.Immune checkpoint blockade and chimeric antigen receptor(CAR)-T cell-based therapies have achieved remarkable success in recent decades,thus placing the host immune response in the spotlight as a potential new approach in antitumor therapy.

Designing a risk prognosis model based on natural killer cell-linked genes to accurately evaluate the prognosis of gastric cancer

Background:This study was aimed at identifying natural killer(NK)cell-related genes to design a risk prognosis model for the accurate evaluation of gastric cancer(GC)prognosis.Methods:We obtained NK cell-related genes from various databases,followed by Cox regression analysis and molecular typing to identify prognostic genes.Various immune algorithms and enrichment analyses were used to investigate the mutations,immune status,and pathway variations among different genotypes.The key prognostic genes were assessed using the least absolute shrinkage and selection operator(Lasso)regression analysis and univariate Cox regression analysis.Thereafter,the risk score(RS)prognosis model was constructed based on the selected important prognostic genes.A Receiver Operating Characteristics(ROC)curve was plotted for analyzing the robustness of the model.Subsequently,the decision and calibration curves were used for assessing the reliability and prediction accuracy of the proposed model.The‘pRRophetic’R software package was utilized for predicting the half-maximal inhibitory concentration(IC50)of immunotherapy and chemotherapy drugs.Results:We screened 21 prognostic genes and three molecular subtypes and found that the C1 subtype had the worst prognosis.Further,the pathways promoting tumor proliferation,such as epithelial-mesenchymal transition were significantly up-regulated.The results also showed that the macrophages in the M2 stage were significantly infiltrated in the C1 subtype,and there was significant overexpression in the C1 subtype,accompanied by a severe inflammatory reaction.The C1 was highly sensitive to drugs like 5-fluorouracil and paclitaxel.The ROC,calibration curve,and decision curve showed that the risk model was robust and strongly reliable.Conclusion:Overall,our proposed NK cell-related RS model can be used as a more accurate prediction index for GC patients,providing a valuable contribution to personalized medicine.

Establishment of a prognostic model related to tregs and natural killer cells infiltration in bladder cancer

BACKGROUND Regulatory T cells(Tregs)and natural killer(NK)cells play an essential role in the development of bladder urothelial carcinoma(BUC).AIM To construct a prognosis-related model to judge the prognosis of patients with bladder cancer,meanwhile,predict the sensitivity of patients to chemotherapy and immunotherapy.METHODS Bladder cancer information data was obtained from The Cancer Genome Atlas and GSE32894.The CIBERSORT was used to calculate the immune score of each sample.Weighted gene co-expression network analysis was used to find genes that will have the same or similar expression patterns.Subsequently,multivariate cox regression and lasso regression was used to further screen prognosis-related genes.The prrophetic package was used to predict phenotype from gene expression data,drug sensitivity of external cell line and predict clinical data.RESULTS The stage and risk scores are independent prognostic factors in patients with BUC.Mutations in FGFR3 lead to an increase in Tregs percolation and affect the prognosis of the tumor,and additionally,EMP1,TCHH and CNTNAP3B in the model are mainly positively correlated with the expression of immune checkpoints,while CMTM8,SORT1 and IQSEC1 are negatively correlated with immune checkpoints and the high-risk group had higher sensitivity to chemotherapy drugs.CONCLUSION Prognosis-related models of bladder tumor patients,based on Treg and NK cell percolation in tumor tissue.In addition to judging the prognosis of patients with bladder cancer,it can also predict the sensitivity of patients to chemotherapy and immunotherapy.At the same time,patients were divided into high and low risk groups based on this model,and differences in genetic mutations were found between the high and low risk groups.

Intestinal natural killer/T-cell lymphoma presenting as a pancreatic head space-occupying lesion:A case report

BACKGROUND Intestinal natural killer/T-cell lymphoma(NKTCL)is a rare and aggressive non-Hodgkin’s lymphoma,and its occurrence is closely related to Epstein-Barr virus infection.In addition,the clinical symptoms of NKTCL are not obvious,and the specific pathogenesis is still uncertain.While NKTCL may occur in any segment of the intestinal tract,its distinct location in the periampullary region,which leads clinicians to consider mimics of a pancreatic head mass,should also be addressed.Therefore,there remain huge challenges in the diagnosis and treatment of intestinal NKTCL.CASE SUMMARY In this case,we introduce a male who presented to the clinic with edema of both lower limbs,accompanied by diarrhea,and abdominal pain.Endoscopic ultrasound(EUS)showed well-defined homogeneous hypoechoic lesions with abundant blood flow signals and compression signs in the head of the pancreas.Under the guidance of EUS-fine needle biopsy(FNB)with 19 gauge or 22 gauge needles,combined with multicolor flow cytometry immunophenotyping(MFCI)helped us diagnose NKTCL.During treatments,the patient was prescribed the steroid(dexamethasone),methotrexate,ifosfamide,L-asparaginase,and etoposide chemotherapy regimen.Unfortunately,he died of leukopenia and severe septic shock in a local hospital.CONCLUSION Clinicians should enhance their understanding of NKTCL.Some key factors,including EUS characteristics,the right choice of FNB needle,and combination with MFCI,are crucial for improving the diagnostic rate and reducing the misdiagnosis rate.

Diffuse large B-cell lymphoma successfully treated with amplified natural killer therapy alone: A case report

BACKGROUND The prognosis of patients with advanced diffuse large B-cell lymphoma(DLBCL)is poor,with a 5-year survival rate of approximately 50%.The mainstay of treatment is multidrug combination chemotherapy,which has been associated with serious side effects.Amplified natural killer(ANK)cell therapy amplifies and activates natural killer(NK)cells to attack only malignant tumors.As ANK cells attack programmed death ligand 1(PD-L1)-positive tumor cells,ANK therapy is considered effective against adult T-cell lymphoma and malignant lymphoma.CASE SUMMARY Herein,we report a case of an older patient with advanced DLBCL who was successfully treated with ANK immunotherapy.A 91-year-old female visited our hospital with sudden swelling of the right axillary lymph node in April 2022.The patient was diagnosed with stage II disease,given the absence of splenic involvement or contralateral lymphadenopathy.ANK therapy was administered.Six rounds of lymphocyte sampling were performed on July 28,2022.To reduce the occurrence of side effects,the six samples were diluted by half to obtain 12 samples.Cultured NK cells were administered twice weekly.The treatment efficacy was evaluated by performing computed tomography and serological tests every 1 or 2 mo.The treatment suppressed lesion growth,and the antitumor effect persisted for several months.The patient experienced mild side effects.PD-L1 immunostaining was positive,indicating that the treatment was highly effective.CONCLUSION ANK therapy can be used as a first-line treatment for malignant lymphoma;the PD-L1 positivity rate can predict treatment efficacy.

Intrahepatic natural killer T cell populations are increased in human hepatic steatosis

AIM: To determine if natural killer T cell (NKT) populations are affected in nonalcoholic fatty liver disease (NAFLD). METHODS: Patients undergoing bariatric surgery underwent liver biopsy and blood sampling during surgery. The biopsy was assessed for steatosis and immunocyte infiltration. Intrahepatic lymphocytes (IHLs) were isolated from the remainder of the liver biopsy, and peripheral blood mononuclear cells (PBMCs) were isolated from the blood. Expression of surface proteins on both IHLs and PBMCs were quantified using flow cytometry. RESULTS: Twenty-seven subjects participated in thisstudy. Subjects with moderate or severe steatosis had a higher percentage of intrahepatic CD3+/CD56+ NKT cells (38.6%) than did patients with mild steatosis (24.1%, P = 0.05) or those without steatosis (21.5%, P = 0.03). Patients with moderate to severe steatosis also had a higher percentage of NKT cells in the blood (12.3%) as compared to patients with mild steatosis (2.5% P = 0.02) and those without steatosis (5.1%, P = 0.05). CONCLUSION: NKT cells are significantly increased in the liver and blood of patients with moderate to severe steatosis and support the role of NKT cells in NAFLD.

Role natural killer group 2D-ligand interactions in hepatitis B infection

Hepatitis B virus （HBV） infection is the leading causeof liver disease and hepatocellular carcinoma （HCC）worldwide, in spite of prophylactic vaccination andantiviral treatment modalities. The immunopathogenesisof HBV infection has been intensively studied and ispropelled by complex interactions between the virus andthe host immune system. Natural killer group 2D （NKG2D）is a well-characterized activating receptor, expressed onnatural killer （NK） cells, NK T cells and CD8＋ cytotoxic Tcells. This receptor is present in both humans and miceand binds to a diverge family of ligands that resemble theMHC-class Ⅰ molecules. Increasing evidence shows thatNKG2D-ligand interactions are critical in the establishmentof HBV persistence and the development of liver injuryand HCC. The expression of NKG2D ligands dependson the presence of several polymorphisms and is alsomodulated post-transcriptionally by HBV. While it isknown that HBV circumvents host’s innate immunityvia the NKG2D pathway but the exact mechanismsinvolved are still elusive. This letter discusses previousaccomplishments on the role of NKG2D ligand regulationin the development of chronic HBV, liver injury and HCC.Key words： Hepatitis B virus; Natural killer group 2Dreceptor; Natural killer cells; MHC class I polypeptiderelatedchain A; Hepatocellular carcinoma

Isolation and identification of a marine killer yeast strain YF07b and cloning of the gene encoding killer toxin from the yeast

It was found that the marine yeast strain YF07b could secrete a large amount of killer toxin against a pathogenic yeast strain WCY which could cause milky disease in Portunus trituberculcttus. The marine yeast strain YF07b was identified to be Pichia anomala according to the results of routine yeast identification and 18S rDNA and ITS sequences. The gene encoding killer toxin in the marine yeast strain YF07b was amplified by PCR technology. After sequencing, the results show that an open reading frame, consisting of 1 281 bp, encoded a presumed protein of 427 amino acids. The sequence of the cloned gene was found to have 99% match with that of the gene encoding killer toxin in Pichia anomalas strain K. A signal peptide including 17 amino acids appeared in the N-terminal domain of the killer toxin. Therefore, the mature protein consisted of 410 amino acids, its molecular mass was estimated to be 47.4 ku and its isoelctronic point was 4.5.

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.

线粒体靶向KillerRed增强辐射诱导HeLa细胞自噬作用及其机制

目的:探讨线粒体靶向KillerRed(mtKR)增强辐射诱导HeLa细胞线粒体失能及细胞自噬作用,并阐明其相关分子机制。方法:线粒体靶向质粒PTEN诱导激酶1(Pink1)-mtKR转染HeLa细胞后,进行可见光和4 Gy X射线照射,实验分为对照组、空载体组、Pink1-mtKR组、对照+4 Gy X射线照射组、空载体+4 Gy X射线照射组和Pink1-mtKR+4 Gy X射线照射组。X线照射后24 h,采用流式细胞术检测线粒体膜电位(MMP)和细胞自噬率,采用生化试剂盒检测线粒体呼吸链复合物Ⅰ和Ⅲ水平,采用Western blotting法检测自噬分子P62、Pink1、帕金蛋白(parkin)和线粒体外膜转换酶20(Tom20)的表达量。结果:Pink1-mtKR瞬时转染HeLa细胞后,给予可见光联合4 Gy X射线照射,与对照组比较,Pink1-mtKR组细胞MMP、线粒体呼吸链复合物Ⅰ和Ⅲ水平均明显降低(P<0.05),细胞自噬率明显升高(P<0.05),Pink1-mtKR+4 GyX射线照射组细胞MMP、线粒体呼吸链复合物Ⅰ和Ⅲ水平进一步降低(P<0.05),自噬率进一步升高(P<0.05)。与对照组比较,Pink1-mtKR组和Pink1-mtKR+4 Gy X射线照射组细胞总蛋白中Pink1和parkin蛋白表达量无明显变化,而P62蛋白表达量增加,Pink1-mtKR组和Pink1-mtKR+4 Gy X射线照射组细胞线粒体蛋白中Pink1、parkin和Tom 20蛋白表达量均明显增加。结论:mtKR可增强辐射诱导的线粒体失能和自噬,其机制可能涉及到Pink1/parkin自噬通路的调控。

Why natural killer cells in triple negative breast cancer?

The triple-negative subtype of breast cancer(TNBC)has the bleakest prognosis,owing to its lack of either hormone receptor as well as human epidermal growth factor receptor 2.Henceforth,immunotherapy has emerged as the front-runner for TNBC treatment,which avoids potentially damaging chemotherapeutics.However,despite its documented association with aggressive side effects and developed resistance,immune checkpoint blockade continues to dominate the TNBC immunotherapy scene.These immune checkpoint blockade drawbacks necessitate the exploration of other immunotherapeutic methods that would expand options for TNBC patients.One such method is the exploitation and recruitment of natural killer cells,which by harnessing the innate rather than adaptive immune system could potentially circumvent the downsides of immune checkpoint blockade.In this review,the authors will elucidate the advantageousness of natural killer cell-based immuno-oncology in TNBC as well as demonstrate the need to more extensively research such therapies in the future.

The effects of stereotactic body radiotherapy on peripheral natural killer and CD3~+CD56~+ NKT-like cells in patients with hepatocellular carcinoma

Background: Both natural killer(NK) and CD3+CD56+ natural killer T(NKT)-like cells play critical roles in the antitumor response. This study aimed to explore the effects of stereotactic body radiotherapy(SBRT) on peripheral NK and NKT-like cells in patients with hepatocellular carcinoma(HCC), and to identify possible surface markers on these cells that correlate with the prognosis. Methods: Twenty-five HCC patients were prospectively enrolled in our study, and 10 healthy individuals were served as healthy controls. Flow cytometry was used to determine the counts and the percentages of peripheral NK and NKT-like cells, cells with certain receptors, and cells with intracellular interferon-γand TNF-α secretion at different time points, including time points of prior to SBRT, at post-SBRT, and 3-month and 6-month after treatment. The Kaplan-Meier method with the log-rank test was applied for survival analysis. Results: The peripheral NKT-like cells was increased at post-SBRT. Meanwhile, elevated levels of inhibitory receptors and reduced levels of activating receptors of NK cells were also observed in NK cells at post-SBRT, but the levels was not significantly different at 3-month and 6-month as compared with the baseline levels. Lower percentage of NKp30+ NK cells before SBRT and higher percentage of CD158b + NK cells after SBRT were associated with poor progression-free survival. In addition, higher percentage of CD3+CD56+ NKT-like cells was associated with a higher overall survival rate in HCC patients. Conclusions: SBRT has an apparent effect on both peripheral NK and CD3+ CD56+ NKT-like cells. Lower percentage of NKp30 + NK cells before SBRT and higher percentage of CD158b + NK cells after SBRT are correlated with poor patients' PFS. Higher percentage of CD3+ CD56+ NKT-like cells is associated with higher OS in HCC patients.

Succinct and Concise Style, Profound and Subtle Theme—An Appreciation of“The Killers”

Hemingway's writing style is unique in the literary world.The basic feature of his works is concise,crisp and implicit.His dialogue has a name of"telegraphic dialogue"."The Killers"is the classic masterpiece of this style,and it is one of the most outstanding works of modern American short stories.This article aims at analyzing the theme and the characters of the novel through the dialogues.

A Good Example of Hemingway's Iceberg Principle:The Killers

Hemingway established a well-known literary theory - iceberg principle.He said he always attempted to create his literary works according to this principle.In his opinion,if a prose writer has a pretty clear idea of what he writes about,then he can omit the things he knows,and the readers will strongly feel that what the writer has omitted seems to have been written as long as what he writes is authentic.Hemingway himself once said,"The dignity of movement of an iceberg is due to only one eighth of it being above water."Here,one eighth refers to the information given by the author,and the rest refers to the unwrit ten information that can be acquired in readers'imagination on the basis of the one eighth.The Killers is a good example of Hemingway's iceberg principle.This essay will analyse the characters in it to show how the principle was used in this short story.With no doubt the iceberg principle leaves a large space for the readers to imagine and better understand Hemingway's works.

线粒体靶向KillerRed诱导的ROS增强辐射对HeLa细胞的增殖抑制作用

目的:构建线粒体靶向KillerRed(KR)重组表达载体,探讨可见光照射诱导活性氧(ROS)生成规律及其增强电离辐射对HeLa细胞的增殖抑制作用。方法:利用基因重组技术构建线粒体靶向重组载体plxspflag-Sarm1-KR和plxsp-flag-Sarm1-mCherry。将宫颈癌HeLa细胞分为对照组、plxsp-flag组、plxsp-flag-Sarm1-KR组、4Gy组、plxsp-flag+4Gy组和plxsp-flag-Sarm1-KR+4Gy组。细胞转染24h后,利用荧光显微镜检测mCherry蛋白和细胞色素C氧化酶Ⅳ(COXⅣ)蛋白表达水平;可见光照射后利用DCFH-DA探针检测平均荧光强度(MFI),表示ROS生成水平;4Gy X射线照射后,利用CCK-8试剂盒检测细胞增殖活性。结果:构建载体经测序鉴定并与GenBank序列比对,表明线粒体靶向融合表达载体plxsp-flag-Sarm1-KR(mCherry)构建成功。转染HeLa细胞后,荧光显微镜下可见mCherry蛋白与线粒体示踪COXⅣ蛋白具有相同的定位。ROS生成水平,对照组和plxsp-flag组在可见光照射10、30和60min后掺入探针,掺入探针10、30和60min后MFI无明显变化(P>0.05);plxsp-flag-Sarm1-KR组MFI呈时间依赖性增加,与对照组比较,plxsp-flag-Sarm1-KR组可见光照射10和30min后掺入探针,掺入探针60min后MFI明显增加(P<0.05);可见光照射60min后掺入探针,掺入探针30和60min后plxsp-flag-Sarm1-KR组MFI明显降低(P<0.05)。与对照组比较,plxsp-flag组细胞增殖活性无明显变化(P>0.05),10和24h时plxsp-flag-Sarm1-KR组细胞增殖活性明显降低(P<0.05),10h时4Gy组和plxsp-flag+4Gy组细胞增殖活性明显降低(P<0.01),10、24和48h时plxsp-flagSarm1-KR+4Gy组细胞增殖活性明显降低(P<0.05或P<0.01);与plxsp-flag-Sarm1-KR组和4Gy组比较,plxsp-flag-Sarm1-KR+4Gy组细胞增殖活性明显降低(P<0.05)。结论:成功构建线粒体靶向融合表达载体,所介导的KR蛋白可以诱导ROS产生,并且增强电离辐射对HeLa细胞的增殖抑制作用。

Intraperitoneal perfusion of cytokine-induced killer cells with local hyperthermia for advanced hepatocellular carcinoma

AIM:To study the effect and tolerance of intraperitoneal perfusion of cytokine-induced killer(CIK) cells in combination with local radio frequency(RF) hyperthermia in patients with advanced primary hepatocellular carcinoma(HCC).METHODS:Patients with advanced primary HCC were included in this study.CIK cells were perfused intraperitoneal twice a week,using 3.2 × 10 9 to 3.6 × 10 9 cells each session.Local RF hyperthermia was performed 2 h after intraperitoneal perfusion.Following an interval of one month,the next course of treatment was administered.Patients received treatment until disease progression.Tumor size,immune indices(CD3 +,CD4 +,CD3 + CD8 +,CD3 + CD56 +),alpha-fetoprotein(AFP) level,abdominal circumference and adverse events were recorded.Time to progression and overall survival(OS) were calculated.RESULTS:From June 2010 to July 2011,31 patients diagnosed with advanced primary HCC received intraperitoneal perfusion of CIK cells in combination with local RF hyperthermia in our study.Patients received an average of 4.2 ± 0.6 treatment courses(range,1-8 courses).Patients were followed up for 8.3 ± 0.7 mo(range,2-12 mo).Following combination treatment,CD4 +,CD3 + CD8 + and CD3 + CD56 + cells increased from 35.78% ± 3.51%,24.61% ± 4.19% and 5.94% ± 0.87% to 45.83% ± 2.48%(P = 0.016),39.67% ± 3.38%(P = 0.008) and 10.72% ± 0.67%(P = 0.001),respectively.AFP decreased from 167.67 ± 22.44 to 99.89 ± 22.05 ng/mL(P = 0.001) and abdominal circumference decreased from 97.50 ± 3.45 cm to 87.17 ± 4.40 cm(P = 0.002).The disease control rate was 67.7%.The most common adverse events were low fever and slight abdominal erubescence,which resolved without treatment.The median time to progression was 6.1 mo.The 3-,6-and 9-mo and 1-year survival rates were 93.5%,77.4%,41.9% and 17.4%,respectively.The median OS was 8.5 mo.CONCLUSION:Intraperitoneal perfusion of CIK cells in combination with local RF hyperthermia is safe,can efficiently improve immunological status,and may prolong survival in HCC patients.

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.

Immunotherapy with dendritic cells and cytokine-induced killer cells for hepatocellular carcinoma: A meta-analysis

BACKGROUND Hepatocellular carcinoma(HCC) has been revealed as the second most common cause of cancer-related deaths worldwide. The introduction of cell-based immunotherapy, including dendritic cells(DCs) and cytokine-induced killer cells(CIKs), has brought HCC patients an effective benefit. However, the efficacy and necessity of cellular immunotherapy after different interventional therapy remains to be further explored.AIM To investigate the efficacy of cellular immunotherapy, involving DCs and CIKs,combined with different conventional treatments of HCC.METHODS We performed a literature search on PubMed and Web of Science up to February15, 2019. Long-term efficacy(overall survival and recurrence) and short-term adverse effects were investigated to assess the effectiveness of immunotherapy with DCs and/or CIKs. Review Manager 5.3 was used to perform the analysis.RESULTS A total of 22 studies involving 3756 patients selected by eligibility inclusion criteria were forwarded for meta-analysis. Combined with the conventional clinical treatment, immunotherapy with DCs and/or CIKs was demonstrated to significantly improve overall survival at 6 mo [risk ratio(RR) = 1.07;95%confidence interval(CI): 1.01-1.13, P = 0.02], 1 year(RR = 1.12;95%CI: 1.07-1.17, P< 0.00001), 3 years(RR = 1.23;95%CI: 1.15-1.31, P < 0.00001) and 5 years(RR =1.26;95%CI: 1.15-1.37, P < 0.00001). Recurrence rate was significantly reduced by cellular immunotherapy at 6 mo(RR = 0.50;95%CI: 0.36-0.69, P < 0.0001) and 1 year(RR = 0.82;95%CI: 0.75-0.89, P < 0.00001). Adverse effect assessment addressed that immunotherapy with DCs and/or CIKs was accepted as a safe,feasible treatment.CONCLUSION Combination immunotherapy with DCs, CIKs and DC/CIK with various routine treatments for HCC was evidently suggested to improve patients’ prognosis by increasing overall survival and reducing cancer recurrence.

Primary site and regional lymph nodeinvolvement are independent prognosticfactors for early？stage extranodal nasal？typenatural killer/T cell lymphoma

Background:Nasal-type extranodal natural killer/T-cell lymphoma(ENKTCL) originates primarily in the nasal cavity or extra-nasal sites within the upper aerodigestive tract.However,it is unclear whether the primary site can serve as an independent prognostic factor or whether the varying clinical outcomes observed with different primary sites can be attributed merely to their propensities of regional lymph node involvement.The aim of this study was to investigate the prognostic implications of the primary site and regional lymph node involvement in patients with early-stage nasal-type ENKTCL.Methods:To develop a nomogram,we reviewed the clinical data of 215 consecutively diagnosed patients with early-stage nasal-type ENKTCL who were treated in Sun Yat-sen University Cancer Center with chemotherapy and radiotherapy between 2000 and 2011.The predictive accuracy and discriminative ability of the nomogram were determined using a concordance index(C-index) and calibration curve.Results:The 5-year overall survival(OS) and progression-free survival(PFS) rates of patients with nasal ENKTCL were higher than those of patients with extra-nasal ENKTCL(OS:68.2%vs.46.0%,P = 0.030;PFS:53.4%vs.26.6%,P = 0.010).The 5-year OS and PFS rates of patients with Ann Arbor stage IE ENKTCL were higher than those of patients with Ann Arbor stage HE ENKTCL(OS:66.3%vs.59.2%,P = 0.003;PFS:51.4%vs.40.3%,P = 0.009).Multivariate analysis showed that age >60 years,ECOG performance status score >2,elevated lactate dehydrogenase(LDH) level,extranasal primary site,and regional lymph node involvement were significantly associated with lower 5-year OS rate;age >60 years,elevated LDH level,extra-nasal primary site,and regional lymph node involvement were significantly associated with lower 5-year PFS rate.The nomogram included the primary site and regional lymph node involvement based on multivariate analysis.The calibration curve showed good agreement between the predicted and actual 5-year OS and PFS rates,and the C-indexes of the nomogram for the OS and PFS rates were 0.697 and 0.634,respectively.Conclusions:The primary site and regional lymph node involvement are independent prognostic factors for earlystage ENKTCL treated with chemotherapy followed by definitive radiotherapy.