Prognostic implications of STK11 with different mutation status and its relationship with tumor-infiltrating immune cells in non-small cell lung cancer.

Background: Mutations in STK11 (STK11Mut) gene may present a negative impact on survival in Non-small Cell Lung Cancer (NSCLC) patients, however, its relationship with immune related genes remains unclear. This study is to unveil whether overexpressed- and mutated-STK11 impact survival in NSCLC and to explore whether immune related genes (IRGs) are involved in STK11 mutations. Methods: 188 NSCLC patients with intact formalin-fixed paraffin-embedded (FFPE) tissue available for detecting STK11 protein expression were included in the analysis. After immunohistochemical detection of STK11 protein, patients were divided into high STK11 expression group (STK11High) and low STK11 expression group (STK11Low), and then Kaplan-Meier survival analysis and COX proportional hazards model were used to compare the overall survival (OS) and progression-free survival (PFS) of the two groups of patients. In addition, the mutation data from the TCGA database was used to categorize the NSCLC population, namely STK11 Mutated (STK11Mut) and wild-type (STK11Wt) subgroups. The difference in OS between STK11Mut and STK11Wt was compared. Finally, bioinformatics analysis was used to compare the differences in IRGs expression between STK11Mut and STK11Wt populations. Results: The median follow-up time was 51.0 months (range 3.0 - 120.0 months) for real-life cohort. At the end of follow-up, 64.36% (121/188) of patients experienced recurrence or metastasis. 64.89% (122/188) of patients ended up in cancer-related death. High expression of STK11 was a significant protective factor for NSCLC patients, both in terms of PFS [HR=0.42, 95% CI= (0.29-0.61), P<0.001] and OS [HR=0.36, 95% CI= (0.25, 0.53), P<0.001], which was consistent with the finding in TCGA cohorts [HR=0.76, 95%CI= (0.65, 0.88), P<0.001 HR=0.76, 95%CI= (0.65, 0.88), P<0.001]. In TCGA cohort, STK11 mutation was a significant risk factor for NSCLC in both lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) histology in terms of OS [HR=6.81, 95%CI= (2.16, 21.53), P<0.001; HR=1.50, 95%CI= (1.00, 2.26), P=0.051, respectively]. Furthermore, 7 IRGs, namely CALCA, BMP6, S100P, THPO, CGA, PCSK1 and MUC5AC, were found significantly overexpressed in STK11-mutated NSCLC in both LUSC and LUAD histology. Conclusions: Low STK11 expression at protein level and presence of STK11 mutation were associated with poor prognosis in NSCLC, and mutated STK11 might probably alter the expression IRGs profiling.

Effects of BRD4 inhibitor JQ1 on the expression profile of super-enhancer related lncRNAs and mRNAs in cervical cancer HeLa cells.

Objective: To investigate the effects of bromine domain protein 4 (BRD4) inhibitor JQ1 on the expression profile of super-enhancer-related lncRNAs (SE-lncRNAs) and mRNAs in cervical cancer (CC) HeLa-cells. Methods: The CCK8 method was implemented to detect the inhibitory effect of JQ1 on HeLa cells and explore the best inhibitory concentration. Whole transcriptome sequencing was performed to detect the changes of lncRNAs and mRNAs expression profiles in cells of the JQ1 treatment group and control group, respectively. The differentially expressed SE-lncRNAs were obtained by matching, while the co-expressed mRNAs were obtained by Pearson correlation analysis. Results: The inhibitory effect of JQ1 on HeLa cell proliferation increased significantly with increasing concentration and treatment time (P < 0.05). Under the experimental conditions of three concentrations of 0.01, 0.1 and 1 µmol/L of JQ1 on HeLa cells at 24, 48, 72 and 120 h, 1 µmol/L of JQ1 at 72 and 120 h had the same cell viability and the strongest cell proliferation inhibition. In order to understand the inhibitory mechanism of JQ1 on HeLa cells, this study analyzed the expression profile differences from the perspective of SE-lncRNAs and mRNAs. A total of 162 SE-lncRNAs were identified, of which 8 SE-lncRNAs were down-regulated and seven SE-lncRNAs were up-regulated. A total of 418 differentially expressed mRNAs related to SE-lncRNAs were identified, of which 395 mRNAs had positive correlation with 12 SE-lncRNAs and 408 mRNAs had negative correlation with 15 SE-lncRNAs. Conclusion: JQ1 can significantly inhibit the proliferation of HeLa cells and affect the expression profile of SE-lncRNAs and mRNAs.

Efficacy and safety of immune checkpoint inhibitors combined with chemotherapy as first-line treatment for extensive-stage small cell lung cancer: a meta-analysis based on mixed-effect models.

Background: Extensive-stage small cell lung cancer (ES-SCLC) is a highly invasive and fatal disease with limited therapeutic options and poor prognosis. Our study aims to systematically evaluate the efficacy and safety of immune checkpoint inhibitors combined with chemotherapy (ICIs+ChT) vs. chemotherapy alone (ChT) in the first-line treatment of ES-SCLC. Methods: A literature search was performed for randomized controlled trials (RCTs) related to "ICIs+ChT" vs. "ChT" in the first-line treatment of ES-SCLC in PubMed, Cochrane Library, Embase, CNKI, and other databases. RevMan 5.4 software was used to perform meta-analyses with hazard ratio (HR) and relative risk (RR). SAS 9.4 software was applied to conduct a mixed-effect model meta-analysis of the survival outcomes and draw survival curves. Results: A total of 2,638 patients with ES-SCLC from 6 RCTs were included, of which 1,341 patients received "ICIs+ChT" and 1,297 received ChT. Based on the meta-analysis results provided by the mixed-effect model, patients receiving the "ICIs+ChT" regimen had a significantly longer overall survival (OS, HR = 0.800, 95% CI = 0.731-0.876, P < 0.001) and progression-free survival (PFS, HR = 0.815, 95% CI = 0.757-0.878, P <0.001) in comparison to those receiving ChT only. Compared with ChT, "ICIs+ChT" did neither improve the objective response rate (ORR, RR = 1.06, 95% CI = 1.00-1.12, P = 0.06) nor did it improve the disease control rate (DCR, RR = 0.97, 95% CI = 0.92-1.03, P = 0.35). Although the incidence of grade 3 to 5 treatment-related adverse events (trAEs) in the "ICIs+ChT" subgroup did not increase (RR = 1.16, 95% CI = 0.97-1.39, P = 0.11), the incidence of grade 3 to 5 immune-related adverse events (irAEs) increased significantly (RR = 4.29, 95% CI = 1.73-10.61, P < 0.00001). Conclusion: ICIs+ChT regimen could significantly prolong OS and PFS in patients with ES-SCLC compared with ChT alone. Although the incidence of irAEs in "ICIs+ChT" is higher than that in the "ChT" subgroup, the incidence of trAEs is similar within the two subgroups. ICIs combined with chemotherapy demonstrated a good choice as first-line treatment for ES-SCLC. Systematic review registration: PROSPERO, identifier: CRD42022348496.

Prediction study of prognostic nutrition index on the quality of life of patients with cervical cancer undergoing radiotherapy and chemotherapy.

Objective: To assess the prognostic nutritional index (PNI) and quality of life (QOL) of patients with cervical cancer (CC) who underwent radiotherapy and chemotherapy and to reveal the effect of PNI on QOL and its prognostic value. Methods: A total of 138 CC patients who underwent radiotherapy and chemotherapy in the Second Affiliated Hospital of Fujian Medical University from January 2020 to October 2022 were selected as the study subjects via convenient sampling. According to the PNI cut-off value of 48.8, they were divided into a high-PNI group and a low-PNI group, and the quality of life of the two groups was compared. The Kaplan-Meier method was used to draw the survival curve, and the Log-Rank test was employed to compare the survival rates of the two groups. Results: The scores of physical functioning and overall QOL in the high-PNI group were significantly higher than those in the low-PNI group (P < 0.05). The scores of fatigue, nausea and vomiting, pain and diarrhea were higher than those in the low-PNI group, and the difference was statistically significant (P < 0.05). The objective response rates were 96.77% and 81.25% in the high-PNI group and the low-PNI group, respectively, and the difference was statistically significant (P = 0.045). The 1-year survival rates of patients with high PNI and low PNI were 92.55% and 72.56% in the high-PNI group and the low-PNI group, respectively; the difference in survival rates was statistically significant (P = 0.006). Conclusion: The overall quality of life of CC patients with low PNI receiving radiotherapy and chemotherapy is lower than that of patients with high PNI. Low PNI reduces the tolerance to radiotherapy and chemotherapy and the objective response rate, which can be used as a prognostic indicator for cervical cancer patients.

Treatment- and immune-related adverse events of immune checkpoint inhibitors in esophageal or gastroesophageal junction cancer: A network meta-analysis of randomized controlled trials.

Objective: To systematically evaluate the safety and adverse event profiles of immune checkpoint inhibitors (ICIs) in patients with esophageal cancer (EPC) or gastroesophageal junction cancer (GEJC). Methods: PubMed, Web of Science, Cochrane Library, and major conference proceedings were systematically searched for all phase II or phase III randomized controlled trials (RCTs) in EPC or GEJC using ICIs. Safety outcomes including treatment-related adverse events (trAEs), immune-related adverse events (irAEs), and serious trAEs were evaluated by network meta-analysis or dichotomous meta-analysis based on the random-effects model. Results: Eleven RCTs involving EPC (five RCTs) and GEJC (six RCTs) were included in the final meta-analysis. NMA showed that placebo was associated with the best safety ranking for grade 3-5 trAEs (SUCRA = 96.0%), followed by avelumab (78.6%), nivolumab (73.9%), ipilimumab (57.0%), and pembrolizumab (56.6%). Conventional pairwise meta-analysis (CPM) showed that ICIs have similar grade 3-5 trAE risk compared with chemotherapy (RR = 0.764, 95% CI: 0.574 to 1.016, I 2 = 95.7%, Z = 1.85, P = 0.065). NMA showed that the general safety of grade 3-5 irAEs ranked from high to low is as follows: ChT (85.1%), placebo (76.5%), ipilimumab (56.0%), nivolumab (48.5%), avelumab (48.4%), camrelizumab (41.8%), pembrolizumab (36.4%), and nivolumab + ipilimumab (21.6%). CPM showed that the rates of grade 3-5 irAEs in the ICI group and the chemotherapy group were 7.35% (154/2,095, 95% CI: [6.23%, 8.47%]) versus 2.25% (42/1,869, 95% CI: [1.58%, 2.92%]), with statistical significance (RR = 3.151, 95% CI = 2.175 to 4.563, Z = 6.07, P = 0.000). The most common irAEs in the ICI group were skin reaction (15.76%, 95% CI: [13.67%, 17.84%]), followed by hypothyroidism (9.73%, 95% CI: [8.07%, 11.39%]), infusion-related reactions (5.93%, 95% CI: [4.29%, 7.58%]), hepatitis (5.25%, 95% CI: [4.28%, 6.22%]), and pneumonitis (4.45%, 95% CI: [3.5%, 5.4%]). Conclusion: Different ICIs had different toxicity manifestations and should not be considered as an entity. Compared with chemotherapy, ICIs were more prone to irAEs, but the overall rates remained low and acceptable. For clinicians, it is important to recognize and monitor the adverse events caused by ICIs for patients with EPC or GEJC.

A novel immune-related radioresistant lncRNAs signature based model for risk stratification and prognosis prediction in esophageal squamous cell carcinoma.

Background and purpose: Radioresistance remains a major reason of radiotherapeutic failure in esophageal squamous cell carcinoma (ESCC). Our study is to screen the immune-related long non-coding RNA (ir-lncRNAs) of radiation-resistant ESCC (rr-ESCC) via Gene Expression Omnibus (GEO) database and to construct a prognostic risk model. Methods: Microarray data (GSE45670) related to radioresistance of ESCC was downloaded from GEO. Based on pathologic responses after chemoradiotherapy, patients were divided into a non-responder (17 samples) and responder group (11 samples), and the difference in expression profiles of ir-lncRNAs were compared therein. Ir-lncRNA pairs were constructed for the differentially expressed lncRNAs as prognostic variables, and the microarray dataset (GSE53625) was downloaded from GEO to verify the effect of ir-lncRNA pairs on the long-term survival of ESCC. After modelling, patients are divided into high- and low-risk groups according to prognostic risk scores, and the outcomes were compared within groups based on the COX proportional hazards model. The different expression of ir-lncRNAs were validated using ECA 109 and ECA 109R cell lines via RT-qPCR. Results: 26 ir-lncRNA genes were screened in the GSE45670 dataset with differential expression, and 180 ir-lncRNA pairs were constructed. After matching with ir-lncRNA pairs constructed by GSE53625, six ir-lncRNA pairs had a significant impact on the prognosis of ESCC from univariate analysis model, of which three ir-lncRNA pairs were significantly associated with prognosis in multivariate COX analysis. These three lncRNA pairs were used as prognostic indicators to construct a prognostic risk model, and the predicted risk scores were calculated. With a median value of 2.371, the patients were divided into two groups. The overall survival (OS) in the high-risk group was significantly worse than that in the low-risk group (p < 0.001). The 1-, 2-, and 3-year prediction performance of this risk-model was 0.666, 0.702, and 0.686, respectively. In the validation setting, three ir-lncRNAs were significantly up-regulated, while two ir-lncRNAs were obviouly down-regulated in the responder group. Conclusion: Ir-lncRNAs may be involved in the biological regulation of radioresistance in patients with ESCC; and the prognostic risk-model, established by three ir-lncRNAs pairs has important clinical value in predicting the prognosis of patients with rr-ESCC.

Engineered triple inhibitory receptor resistance improves anti-tumor CAR-T cell performance via CD56.

The inhibitory receptors PD-1, Tim-3, and Lag-3 are highly expressed on tumor-infiltrating lymphocytes and compromise their antitumor activity. For efficient cancer immunotherapy, it is important to prevent chimeric antigen receptor T (CAR-T)-cell exhaustion. Here we downregulate these three checkpoint receptors simultaneously on CAR-T cells and that show the resulting PTL-CAR-T cells undergo epigenetic modifications and better control tumor growth. Furthermore, we unexpectedly find increased tumor infiltration by PTL-CAR-T cells and their clustering between the living and necrotic tumor tissue. Mechanistically, PTL-CAR-T cells upregulate CD56 (NCAM), which is essential for their effector function. The homophilic interaction between intercellular CD56 molecules correlates with enhanced infiltration of CAR-T cells, increased secretion of interferon-γ, and the prolonged survival of CAR-T cells. Ectopically expressed CD56 promotes CAR-T cell survival and antitumor response. Our findings demonstrate that genetic blockade of three checkpoint inhibitory receptors and the resulting high expression of CD56 on CAR-T cells enhances the inhibition of tumor growth.