The Role of Natural Killer Cells in the Tumor Immune Microenvironment of EBV-Associated Nasopharyngeal Carcinoma.

Endemic nasopharyngeal carcinoma (NPC) is closely associated with the Epstein-Barr virus (EBV), which contributes to tumor development and influences the tumor immune microenvironment (TIME) in NPC. Natural killer (NK) cells, as part of the innate immune system, play a crucial role in responding to viral infections and malignant cell transformations. Notably, NK cells possess a unique ability to target tumor cells independent of major histocompatibility complex class I (MHC I) expression. This means that MHC I-deficient tumor cells, which can escape from effective T cell attack, are susceptible to NK-cell-mediated killing. The activation of NK cells is determined by the signals generated through inhibitory and activating receptors expressed on their surface. Understanding the role of NK cells in the complex TIME of EBV+ NPC is of utmost importance. In this review, we provide a comprehensive summary of the current understanding of NK cells in NPC, focusing on their subpopulations, interactions, and cytotoxicity within the TIME. Moreover, we discuss the potential translational therapeutic applications of NK cells in NPC. This review aims to enhance our knowledge of the role of NK cells in NPC and provide valuable insights for future investigations.

[Drug Resistance Mechanism and Therapeutic Strategy of Targeted Therapy of 
Non-small Cell Lung Cancer with MET Alterations].

Mesenchymal to epithelial transition factor (MET) gene alterations involve in the proliferation, invasion, and metastasis of non-small cell lung cancer. MET-tyrosine kinase inhibitors (TKIs) have been approved to treat non-small cell lung cancer with MET alterations, and resistance to these TKIs is inevitable. Molecular mechanisms of resistance to MET-TKIs are completely unclear. The review focused on potential mechanisms of MET-TKIs resistance and therapeutics strategies to delay and prevent resistance.
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Shoot Organogenesis and Regeneration from Leaf Seedlings of Diospyros oleifera Cheng.

Persimmons (Diospyros) are economically important trees that are widely cultivated for wood production in China, and Diospyros oleifera Cheng is the main persimmon grafting stock. However, an efficient tissue culture system has not been perfected for D. oleifera due to the limits of proliferation and rooting cultures. Therefore, this study examined the effects of different plant growth regulators and concentrations on the primary culture of young embryos, induction of leaf callus, differentiation of adventitious shoots, and rooting culture of D. oleifera. The optimal formula for young embryo germination was 1/2 Murashige and Skoog (MS) medium containing 0.5 mg/L gibberellic acid (GA3); after 25 days, the sprouting rate of the young embryos was 67.3%. The best medium for leaf callus induction was 1/2MS medium containing 2.0 mg/L of 6-benzylaminopurine (6-BA) and 0.5 mg/L of naphthaleneacetic acid (NAA), and the callus induction rate was 88.9%. Then, the callus was transferred to 1/2MS medium containing 2.0 mg/L of zeatin (ZT), 0.5 mg/L of NAA, and 2.0 mg/L of thidiazuron (TDZ) to induce adventitious shoots; after 25 days, 5.4 buds were produced per explant, and the induction rate of the adventitious shoots was 88.3%. The adventitious shoots were transferred to 1/2MS medium containing 2.0 mg/L of ZT, 2.0 mg/L of 6-(γ,γ-dimethylallylamino)purine (2iP), and 0.1 mg/L of indole acetic acid (IAA) for the proliferation culture, for which the multiplication coefficient approached 7.5. After multiplication, the adventitious shoots were inoculated into 1/2MS medium containing 1.0 mg/L of indole butyric acid (IBA), 0.5 mg/L of NAA, and 1.0 mg/L of kinetin (KT); the rooting rate was 60.2%, and the average number of roots was 6.9.

Expression of phosphoglycerate-mutase 1 in colorectal cancer tissues and its effects on the prognosis and malignant biological behaviors of cancer cells / 中国肿瘤生物治疗杂志

@#[摘 要] 目的：探讨结直肠癌（CRC）组织中磷酸甘油酸变位酶1（PGAM1）的表达及其与患者预后的关系，研究PGAM1对CRC细胞增殖、迁移和侵袭的影响。方法：选择2003年3月至2008年11月间在天津医科大学肿瘤医院手术切除的30例CRC患者的肿瘤组织标本及临床资料，采用免疫组织化学染色法检测CRC组织中PGAM1蛋白的表达，分析PGAM1表达与患者临床病理特征的关系，Kaplan-Meier生存分析法比较PGAM1高表达与低表达患者的OS、PFS来评价PGAM1表达与患者预后的关系。利用RNA干扰技术分别将si-PGAM1及si-NC质粒转染至HCT-116和SW480细胞，WB法检测转染细胞中PGAM1蛋白的表达水平，CCK-8、Transwell实验分别检测敲低PGAM1对CRC细胞增殖、迁移和侵袭的影响。结果：30例CRC组织中PGAM1阳性染色定位于CRC细胞的细胞质，其中33.3%（10/30例）呈高表达。虽然PGAM1高表达与CRC患者年龄、性别、组织学类型、肿瘤大小、淋巴结转移、远处转移及临床TNM分期无关（均P>0.05），但是PGAM1高表达与低表达患者相比其OS、PFS显著缩短。在CRC细胞中敲低PGAM1后，细胞的增殖、迁移和侵袭能力均显著降低（均P<0.05）。结论：CRC组织中PGAM1呈高表达，PGAM1高表达的患者预后较差；敲低PGAM1后细胞的增殖、迁移及侵袭能力均显著降低，提示PGAM1可能是CRC患者预后的生物标志物。

Pathologic complete response to immune checkpoint inhibitor in a stage IIIB ovarian clear cell carcinoma patient with POLE mutation resistant to platinum-based chemotherapy: a case report.

Background: Ovarian clear cell carcinoma (OCCC) is a subtype of ovarian cancer with unique features at histological and molecular levels. The prevalence of OCCC is higher in east Asia than in Western countries. As cases are usually chemo-resistant, treatment effects of platinum-based chemotherapy are not satisfactory, especially for patients with stage III or IV disease. Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of patients with advanced-stage cancers. However, whether advanced OCCC patients benefit from ICIs remains elusive. Case Description: Herein, we report a Chinese patient with stage IIIB inoperable OCCC who was resistant to platinum-based chemotherapy and anlotinib. Next-generation sequencing (NGS) revealed a pathogenic polymerase epsilon (POLE) P286R mutation and a high level of tumor mutation burden (TMB) in tissue and plasma samples. The ICI sintilimab was then used with bevacizumab as third-line treatment. Tumor reduction was observed, and the patient underwent surgical resection which indicated a pathologic complete response (pCR). Maintenance therapy with sintilimab and bevacizumab was applied, and the patient has achieved overall survival (OS) of 35 months since the diagnosis. They have also achieved a progression-free survival (PFS) of 29 months since commencing ICI treatment and have been disease-free for 24 months after surgical resection. Conclusions: The treatment effect of ICI in POLE-mutant OCCC patients has been rarely reported. The treatment benefits observed in the stage IIIB OCCC patient who was resistant to platinum-based chemotherapy may be associated with the presence of POLE mutation and a high level of TMB. Comprehensive genomic profiling could contribute to appropriate treatment decisions for OCCC.

A Phase IB Trial of Autologous Cytokine-Induced Killer Cells in Combination with Sintilimab, Monoclonal Antibody Against Programmed Cell Death-1, plus Chemotherapy in Patients with Advanced Non-Small-Cell Lung Cancer.

INTRODUCTION: Can the Cytokine-induced killer (CIK) cells in combination with immune checkpoint inhibitor further improve the efficacy of chemotherapy in non-small cell lung cancer (NSCLC) patients? What are the adverse reactions of this combination therapy? But these problems are not clear. Therefore, we conducted a phase 1b trial to evaluate the safety and efficacy of autologous CIK cells therapy combined with Sintilimab, antibody against programmed cell death-1, plus chemotherapy in untreated, advanced NSCLC patients. PATIENTS AND METHODS: Patients with stage IIIB/IIIC/IV NSCLC received Sintilimab, platinum-based doublet chemotherapy, and CIK cells every 3 weeks for 4 cycles, then maintenance treatment with Sintilimab in squamous and with Sintilimab plus pemetrexed in non-squamous NSCLC until disease progression or unacceptable toxicity or 2 years. The primary endpoints were safety and objective response rate (ORR). RESULTS: Thirty-four patients received the treatment. 94.1% of patients experienced treatment-related adverse events (TRAEs). Grade 3 or greater TRAEs occurred in 64.7% of patients. One (2.9%) patient died of grade 5 immune-related pneumonia. The ORR and DCR were 82.4% (95% CI, 65.5%-93.2%) and 100.0% (95% CI, 89.7%-100.0%), respectively. Objective responses were evaluated in 14 of 15 non-squamous patients (93.3%; 95% CI, 68.1%-99.8%) and in 14 of 19 squamous patients (73.7%; 95% CI, 48.8%-90.9%). Median PFS was 19.3 months (95% CI, 8.3 months to not available). CONCLUSION: Autologous CIK cells immunotherapy in combination with Sintilimab plus chemotherapy was well tolerable and showed encouraging efficacy in patients with previously untreated, advanced NSCLC (ClinicalTrials.gov number, NCT03987867).

Autologous cytokine-induced killer (CIK) cells enhance the clinical response to PD-1 blocking antibodies in patients with advanced non-small cell lung cancer: A preliminary study.

BACKGROUND: Programmed death-1 (PD-1) blocking antibodies have been shown to improve progression-free survival (PFS) and overall survival in a subset of patients with non-small cell lung cancer (NSCLC). However, the objective response rate with these agents remains low, and the vast majority of NSCLC patients require alternative combination treatment regimens to prolong their survival. The purpose of this study was to evaluate the clinical efficacy of autologous cytokine-induced killer (CIK) cell infusions combined with PD-1 blocking antibodies in patients with NSCLC. METHODS: In this preliminary study, we investigated the safety and immune function effectiveness of PD-1 blockade antibodies pembrolizumab or nivolumab administered in combination with or without autologous CIK cell infusions in 18 patients with advanced NSCLC. The peripheral blood mononuclear cells were isolated from these patients and the expression level of some cell surface molecules like PD-1 were detected using flow cytometry to reflect the effectiveness of this combination regimen. RESULTS: No treatment-related deaths occurred in either cohort. In comparison with the pretreatment level, CD3+ CD56+ CD16+ T cells were significantly increased with the combination therapy, while myeloid-derived suppressor cells were significantly increased with PD-1 blocking antibody therapy alone but not with combination therapy. Although the serum interleukin-4 level was downregulated following treatment with the combination regimen, interferon-γ levels were unchanged. CONCLUSIONS: The purpose of this clinical study was to report the clinical efficacy and lack of exacerbated autoimmune adverse events with a combination of PD-1 blockade and CIK cell infusions in patients with advanced NSCLC, further supporting assessments of this combination in future clinical trials.

Consistency of genotyping data from simultaneously collected plasma circulating tumor DNA and tumor-DNA in lung cancer patients.

BACKGROUND: To clarify the rate of concordance between the results of concurrent sequencing of circulating tumor DNA (ctDNA) and tumor tissue samples based in clinic settings, and to explore potential factors influencing consistency. METHODS: A retrospective analysis of 27 patients with lung cancer who underwent gene sequencing at the Department of Biotherapy of Tianjin Medical University Cancer Hospital from February 2016 to April 2019, was conducted by synchronous sequencing of tumor and plasma DNA samples and the concordance of mutations in nine known driver genes was calculated. RESULTS: The overall concordance, sensitivity, and specificity for sequencing driver genes in plasma samples, were 85.2%, 87.0%, and 75%, respectively, relative to tumor samples. Concordance was 100% in patients with bone metastases, while the rate in those without bone metastases was 69.2%. Moreover, in patients where both the driver gene and TP53 mutations in plasma were detected, the findings of plasma sequencing of the driver gene were identical to those of tumor sequencing (concordance: 100%). CONCLUSIONS: Overall, our data show that circulating tumor DNA (ctDNA) was able to identify 75% of the identical information in driver genes, with higher rates of concordance in lung cancer patients with bone metastases or TP53 mutation-positive plasma samples.

Phosphoglyceric acid mutase-1 contributes to oncogenic mTOR-mediated tumor growth and confers non-small cell lung cancer patients with poor prognosis.

As a hallmark of cancer, the Warburg effect (aerobic glycolysis) confers a selective advantage for the survival and proliferation of cancer cells. Due to frequent aberration of upstream proto-oncogenes and tumor suppressors, hyperactive mammalian/mechanistic target of rapamycin (mTOR) is a potent inducer of the Warburg effect. Here, we report that overexpression of a glycolytic enzyme, phosphoglyceric acid mutase-1 (PGAM1), is critical to oncogenic mTOR-mediated Warburg effect. mTOR stimulated PGAM1 expression through hypoxia-inducible factor 1α-mediated transcriptional activation. Blockage of PGAM1 suppressed mTOR-dependent glycolysis, cell proliferation, and tumorigenesis. PGAM1 expression and mTOR activity were positively correlated in non-small cell lung cancer (NSCLC) tissues and PGAM1 abundance was an adverse predictor for patient survival. PGAM1 is thus a downstream effector of mTOR signaling pathway and mTOR-PGAM1 signaling cascade may contribute to the development of Warburg effect observed in cancer. We consider PGAM1 as a novel prognostic biomarker for NSCLC and a therapeutic target for cancer.

Paenibacillus polymyxa NSY50 suppresses Fusarium wilt in cucumbers by regulating the rhizospheric microbial community.

Paenibacillus polymyxa (P. polymyxa) NSY50, isolated from vinegar residue substrate, suppresses the growth of Fusarium oxysporum in the cucumber rhizosphere and protects the host plant from pathogen invasion. The aim of the present study was to evaluate the effects of NSY50 application on cucumber growth, soil properties and composition of the rhizospheric soil microbial community after exposure to Fusarium oxysporum. Bacterial and fungal communities were investigated by Illumina sequencing of the 16S rRNA gene and the internal transcribed spacer (ITS) regions (ITS1 and ITS2). The results showed that NSY50 effectively reduced the incidence of Fusarium wilt (56.4%) by altering the soil physico-chemical properties (e.g., pH, Cmic, Rmic, total N and Corg) and enzyme activities, especially of urease and ß-glucosidase, which were significantly increased by 2.25- and 2.64-fold, respectively, relative to the pathogen treatment condition. More specifically, NSY50 application reduced the abundance of Fusarium and promoted potentially beneficial groups, including the Bacillus, Actinobacteria, Streptomyces, Actinospica, Catenulispora and Pseudomonas genera. Thus, our results suggest that NSY50 application can improve soil properties, shift the microbial community by increasing beneficial strains and decreasing pathogen colonization in the cucumber rhizosphere, and reduce the occurrence of cucumber Fusarium wilt, thereby promoting cucumber growth.

Immunotherapy for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common type of hepatic malignancies, with poor prognosis. Treatment for HCC are limited, especially for patients with advanced disease who are not eligible for curative hepatectomy or hepatic transplantation. Mechanisms of immune response during tumor development have been investigated for decades. The efficacy and safety of immunotherapy have also been tested in clinical treatment of malignancies. Here we reviewed the immunotherapy strategies for HCC, as well as the particularity of liver immune system and the immune tolerance of HCC. Vaccines, adaptive therapy, immune checkpoint blockades and cytokines are included. We hope this review will give us an integral concept on HCC immunotherapy and help the readers to understand the mechanism of immune tolerance in liver cancer.