Revolutionizing tumor immunotherapy:unleashing the power of progenitor exhausted T cells

In exploring persistent infections and malignancies, a distinctive subgroup of CD8^(+) T cells, progenitor exhausted CD8^(+) T(Tpex) cells, has been identified. These Tpex cells are notable for their remarkable self-renewal and rapid proliferation abilities. Recent strides in immunotherapy have demonstrated that Tpex cells expand and differentiate into responsive exhausted CD8^(+) T cells, thus underscoring their critical role in the immunotherapeutic retort. Clinical examinations have further clarified a robust positive correlation between the proportional abundance of Tpex cells and enhanced clinical prognosis. Tpex cells have found noteworthy applications in the formulation of inventive immunotherapeutic approaches against tumors. This review describes the functions of Tpex cells in the tumor milieu, particularly their potential utility in tumor immunotherapy. Precisely directing Tpex cells may be essential to achieving successful outcomes in immunotherapy against tumors.

Side Effects during Treatment of Advanced Gastric Carcinoma by Chemotherapy Combined with CIK-cell Transfusion in Elderly People

OBJECTIVE To study the side effects and therapeutic results of autologous cytokine-induced killer （CIK） cell treatment in elderly patients with advanced gastric cancer. METHODS CIK cells were induced and cultured using biotechnics in vitro, and then the cells were infused back into the patients. Sixty elderly gastric cancer patients treated by chemotherapy （FOLFOX4 protocol） were followed-up. Among them, 29 patients were treated with CIK cells during application of chemotherapy. Short-term curative effects and adverse events from the CIK transfusion and chemotherapy were observed. RESULTS Eight cases developed partial remission （PR）, 9 cases moderate remission （MR）, 7 cases stable disease （SD） and 5 cases progressive disease （PD）. Out of a total of 29 patients who received chemotherapy combined with autologous CIK therapy, the total remission rate （PR ＋ MR） was 58.6%. The total remission rate following chemotherapy alone was 45.2%, including 5 PR cases, 9 MR cases, 7 SD cases, and 10 PD cases. There was a relatively lower rate of severe chemotherapic toxicities in the CIK-cell transfusion group. Side effects of autologous CIK transfusion included chills （13 cases）, fever （9 cases）, nausea and vomiting （1 case） and general malaise （3 cases）. Side effects were treated with conventional therapy resulting in their amelioration. No patients developed shock, blood capillary leakage syndrome, or abnormalities in routine blood, urine, liver and renal function tests.CONCLUSION Adoptive immunotherapy with autologous CIK cells may decrease the clinical signs and symptoms of elderly patients who suffer from advanced gastric cancer. Adverse reactions of patients can be alleviated by conventional therapy. Autologous CIK-cell transfusion may improve endurance to chemotherapy.

High expression of CD11c indicates favorable prognosis in patients with gastric cancer

AIM: To determine the relationship between CD11 c expression level and prognosis in patients with gastric cancer(GC).METHODS: This retrospective survival study was performed from July 31,2008 to June 30,2014. Our study inclusion criteria included all the patients with GC who underwent surgical resection between January 1998 and December 2009 in the Third Affiliated Hospital of Soochow University. CD11 c expression levels in 140 patients with GC at different UICC stages were evaluated using immunohistochemistry,and GC tissues from 16 cases were further verified by q RTPCR. The χ2 test was used to compare the patientand disease-related factors between the low CD11 c expression group and the high expression group. Univariate probabilities of overall survival(OS) and disease-free survival(DFS) were assessed using the Kaplan-Meier method. The log rank test was used to compare survival curves. Different multivariate COX models were used to estimate the association between CD11 c expression and both death and recurrence riskin GC patients.RESULTS: The average CD11 c expression level was 5.1 ± 1.8/high power field(HPF) in 10 gastritis samples,4.5 ± 2.3/HPF in 10 gastric polyp samples and 9.7 ± 6.3/HPF in 140 gastric cancer samples,respectively. The CD11 c expression level was significantly decreased from UICC stage Ⅰ to stage Ⅳ(stage Ⅰ: 16.0 ± 7.4,stage Ⅱ: 10.4 ± 5.5,stage Ⅲ: 9.4 ± 6.1,stage Ⅳ: 5.3 ± 3.2,P < 0.001). Patients in the high CD11 c expression group had a greater 3- and 5-year OS probability and longer median survival time compared with the low CD11 c expression group,(67.7% vs 39.2%; 51.4% vs 29.0%; 67.0 mo vs 28.0 mo; χ2 = 6.80,P = 0.009),and had a greater 3- and 5-year DFS probability and longer median DFS time(63.7% vs 24.0%; 49.1% vs 11.9%; 64.0 mo vs 18.0 mo; χ2 = 15.39,P < 0.001). Patients with high CD11 c high expression had a reduced risk of death(HR = 0.56,95%CI: 0.33-0.98,P < 0.05) and relapse(HR = 0.39,95%CI: 0.23-0.67,P < 0.01) compared with patients with low CD11 c expression after adjustment of potential confounders,with the exception of tumor size. However,the protective effect related to death(HR = 0.90,95%CI: 0.49-1.67,P = 0.749) and relapse(HR = 0.65,95%CI: 0.36-1.19,P = 0.160) disappeared when tumor size was incorporated into the model.CONCLUSION: High expression of CD11 c decreased the risk of death and relapse,and may be regarded as an alternative indicator of favorable prognosis in patients with GC.

Mechanism of T cell regulation by microRNAs

MicroRNAs （miRNAs） are small, non-coding single-stranded RNAs that can modulate target gene expression at post- transcriptional level and participate in cell proliferation, differentiation, and apoptosis. T cells have important functions in acquired immune response; miRNAs regulate this immune response by targeting the mRNAs of genes involved in T cell developmentp proliferationj differentiationp and function. For instancep miR-181 family members function in progression by targeting Bcl2 and CD69, among others. MiR-17 to miR-92 clusters function by binding to CREB 1, PTEN, and Bim. Considering that the suppression ofT cell-mediated immune responses against tumor cells is involved in cancer progression, we should investigate the mechanism by which miRNA regulates T cells to develop new approaches for cancer treatment.

Metabolism of high density lipoproteins in liver cancer

Liver plays a vital role in the production and catabolism of plasma lipoproteins. It depends on the integrity of cellular function of liver, which ensures homeostasis of lipid and lipoprotein metabolism. When liver cancer occurs these processes are impaired and high-density lipoproteins are changed.

B7-H4 Expression and Increased Death Risk of Cancer Patients： A Meta-Analysis

OBJECTIVE The relationship between higher levels of B7-H4 expression and death risk of cancer patients remains to be clarified. In the current study, information from an ordinary scale and those from several outcome scales were combined to make a single estimate. PubMed databases were searched for survival studies on the hazard ratios （HR） of malignant tumors associated with higher B7-H4 expression from 1999 to 2010. METHODS The fixed effect model was used to estimate the combined HRs of six studies. Sensitivity analysis was performed to assess the stability. Publication bias was also estimated. Six studies that meet the inclusion criteria were identified; these studies reported the associations between the higher B7-H4 expression and death risk of cancer patients. RESULTS A 42% increase in death risk was observed in patients with higher B7-H4 expression （HR = 1.42; 95% confidence interval： 1.16-1.72）. Sensitivity analyses found the results robust. The analysis shows that higher levels of B7-H4 expression are associated with the death risk of patients suffering from various cancers. CONCLUSION B7-H4 may be a negative regulatory molecule for antitumor immune responses and a molecular target for tumor immunotherapy.

Review:Lipids changes in liver cancer

Liver is one of the most important organs in energy metabolism. Most plasma apolipoproteins and endogenous lipids and lipoproteins are synthesized in the liver. It depends on the integrity of liver cellular function, which ensures homeostasis of lipid and lipoprotein metabolism. When liver cancer occurs, these processes are impaired and the plasma lipid and lipoprotein patterns may be changed. Liver cancer is the fifth common malignant tumor worldwide, and is closely related to the infections of hepatitis B virus (HBV) and hepatitis C virus (HCV). HBV and HCV infections are quite common in China and other Southeast Asian countries. In addition, liver cancer is often followed by a procession of chronic hepatitis or cirrhosis, so that hepatic function is damaged obviously on these bases, which may significantly influence lipid and lipoprotein metabolism in vivo. In this review we summarize the clinical significance of lipid and lipoprotein metabolism under liver cancer.

N-acetyltransferase 10 promotes colon cancer progression by inhibiting ferroptosis through N4-acetylation and stabilization of ferroptosis suppressor protein 1 (FSP1) mRNA

Background:N-acetyltransferase 10(NAT10)is the only enzyme known tomediate the N4-acetylcytidine(ac4C)modification of mRNA and is crucial formRNA stability and translation efficiency.However,its role in cancer development and prognosis has not yet been explored.This study aimed to examine the possible role of NAT10 in colon cancer.Methods:The expression levels ofNAT10were evaluated by immunohistochemical analyses with a colon cancer tissue microarray,and its prognostic value in patients was further analyzed.Quantitative real-time polymerase chain reaction(qRT-PCR)and Western blotting were performed to analyze NAT10 expression in harvested colon cancer tissues and cell lines.Stable NAT10-knockdown and NAT10-overexpressing colon cancer cell lines were constructed using lentivirus.The biological functions of NAT10 in colon cancer cell lines were analyzed in vitro by Cell Counting Kit-8(CCK-8),wound healing,Transwell,cell cycle,and ferroptosis assays.Xenograft models were used to analyze the effect of NAT10 on the tumorigenesis and metastasis of colon cancer cells in vivo.Dot blotting,acetylated RNA immunoprecipitation-qPCR,and RNA stability analyses were performed to explore the mechanism by which NAT10 functions in colon cancer progression.Results:NAT10 was upregulated in colon cancer tissues and various colon cancer cell lines.This increased NAT10 expression was associated with shorter patient survival.Knockdown of NAT10 in two colon cancer cell lines(HT-29 and LoVo)impaired the proliferation,migration,invasion,tumor formation and metastasis of these cells,whereas overexpression of NAT10 promoted these abilities.Further analysis revealed that NAT10 exerted a strong effect on the mRNA stability and expression of ferroptosis suppressor protein 1(FSP1)in HT-29 and LoVo cells.In these cells,FSP1 mRNA was found to be modified by ac4C acetylation,and this epigenetic modification was associated with the inhibition of ferroptosis.Conclusions:Our study revealed that NAT10 plays a critical role in colon cancer development by affecting FSP1 mRNA stability and ferroptosis,suggesting that NAT10 could be a novel prognostic and therapeutic target in colon cancer.

Randomized,multicenter,open-label trial of autologous cytokine-induced killer cell immunotherapy plus chemotherapy for squamous non-small-cell lung cancer:NCT01631357

Dear Editor,Cytokine-induced killer(CIK)cells have been recognized as a new type of anti-tumor effector cells.CIK cells are a mixture of T lymphocytes.Among them,CD3+/CD56+T cells,which are rare in uncultured peripheral blood,are the main effector cells.CIK cells can proliferate rapidly in vitro,with stronger antitumor activity,broader target tumor spectrum,and lower adverse effect than other reported antitumor effector cells.1 Their ease of production in vitro and antitumor potential have made them suitable candidates for cell therapy regimens in solid and hematopoietic tumor treatments.1,2 Our previous retrospective study showed that the median progression-free survival(PFS)and overall survival(OS)in untreated,advanced non-small-cell lung cancer(NSCLC)patients who received CIK cell immunotherapy plus chemotherapy(13 and 24 months,respectively)were significantly longer than in those who received chemotherapy alone(6 and 10 months,respectively).2 But so far,there is no prospective,multicenter clinical study in lung cancer.Based on our previous study,we designed this randomized,multicenter,open-label trial to further evaluate the clinical efficacy of CIK cell immunotherapy plus chemotherapy in patients with advanced squamous NSCLC(ClinicalTrials.gov number,NCT01631357).

XELOX(capecitabine plus oxaliplatin)plus bevacizumab(anti-VEGF-A antibody)with or without adoptive cell immunotherapy in the treatment of patients with previously untreated metastatic colorectal cancer:a multicenter,open-label,randomized,controlled,phase 3 trial

Fluoropyrimidine-based combination chemotherapy plus targeted therapy is the standard initial treatment for unresectable metastatic colorectal cancer(mCRC),but the prognosis remains poor.This phase 3 trial(ClinicalTrials.gov:NCT03950154)assessed the efficacy and adverse events(AEs)of the combination of PD-1 blockade-activated DC-CIK(PD1-T)cells with XELOX plus bevacizumab as a first-line therapy in patients with mCRC.A total of 202 participants were enrolled and randomly assigned in a 1:1 ratio to receive either first-line XELOX plus bevacizumab(the control group,n=102)or the same regimen plus autologous PD1-T cell immunotherapy(the immunotherapy group,n=100)every 21 days for up to 6 cycles,followed by maintenance treatment with capecitabine and bevacizumab.The main endpoint of the trial was progression-free survival(PFS).The median follow-up was 19.5 months.Median PFS was 14.8 months(95%CI,11.6-18.0)for the immunotherapy group compared with 9.9 months(8.0-11.8)for the control group(hazard ratio[HR],0.60[95%CI,0.40-0.88];p=0.009).Median overall survival(OS)was not reached for the immunotherapy group and 25.6 months(95%CI,18.3-32.8)for the control group(HR,0.57[95%CI,0.33-0.98];p=0.043).Grade 3 or higher AEs occurred in 20.0%of patients in the immunotherapy group and 23.5%in the control groups,with no toxicity-associated deaths reported.The addition of PD1-T cells to first-line XELOX plus bevacizumab demonstrates significant clinical improvement of PFS and OS with well tolerability in patients with previously untreated mCRC.