Baseline Serum Cholesterol Levels Predict the Response of Patients with Advanced Non-Small Cell Lung Cancer to Immune Checkpoint Inhibitor-Based Treatment.

PURPOSE: Although predictive markers of immune checkpoint inhibitor (ICI)-based treatments have been extensively studied, with the exception of programmed death ligand 1 (PD-L1), most are not widely used in the clinic due to poor effects or defective practicability. The aim of this study was to identify those patients with high baseline serum cholesterol who benefit from ICI-based treatments. PATIENTS AND METHODS: Patients with advanced non-small cell lung cancer (NSCLC) treated at Ningbo Medical Center, Li Huili Hospital between August 2017 and December 2019 were enrolled in this retrospective study. The Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) were used to evaluate the efficacy of the ICI-based treatment. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier survival curves and compared using the log rank test. Univariate and multivariate analyses were conducted using the logistic regression analysis and Cox proportional hazards model. A receiver operating characteristic curve was created, and the area under the curve (AUC) was calculated to compare the predictive value of baseline serum cholesterol with PD-L1 expression for patient response to ICI-based treatment. RESULTS: In our cohort of 169 NSCLC patients, the objective response rate (ORR) and disease control rate (DCR) of the treatment were significantly higher in patients with hypercholesterolemia (>5.18 mmol/L) than in those with hypocholesterolemia (ORR: 33.67% vs 14.08%, P=0.004; DCR: 68.37% vs 42.25%, P=0.001). The median PFS was 7.9 months in the hypercholesterolemia group, significantly longer than in the hypocholesterolemia group (4.4 months, 95% CI: 4.620-7.380, P<0.001). The median OS in the two groups were 11 months and 8 months, with 95% CIs of 8.980-10.420 (P<0.001). The AUC for the baseline level of cholesterol was 0.706 (P<0.001), while it was 0.643 (P=0.001) for PD-L1 expression. CONCLUSION: The baseline serum cholesterol level is predictive of a clinical benefit for advanced NSCLC patients who undergo ICI-based treatment, and hence it is a promising prognostic indicator for ICI-based treatment of NSCLC.

c-Myc maintains the self-renewal and chemoresistance properties of colon cancer stem cells.

Cancer stem cells (CSCs) are responsible for cancer formation, recurrence and drug resistance. c-Myc, one of the core markers for stem cells, has recently been considered to serve as a link between malignancy and 'stemness'. However, the precise function of c-Myc in colon CSCs is still unclear. In the present study, a subpopulation of colon CSCs expressing a CD133 surface phenotype was isolated from the human HT-29 cell line, which possess greater tumor sphere-forming efficiency and have higher expression of 'stemness'-associated genes compared with CD133-negative cells. Furthermore, it was demonstrated that c-Myc was highly expressed in CD133+ colon CSCs. Knockdown of c-Myc expression with small interfering RNA in colon CSCs can significantly inhibit tumor sphere formation, reduce the invasive and migratory capacity of CD133+ cells in vitro, and suppress the tumorigenicity of colon CSCs in vivo. In addition, it was suggested that c-Myc silencing may sensitize colon CSCs to chemotherapy-induced cytotoxicity via the downregulation of ABCG2 and ABCB5. These findings support a central role for c-Myc in maintaining the self-renewing and chemoresistant properties of colon CSCs.

[Expression and prognostic value of memory T lymphocyte in patients with non-small cell lung cancer following radiotherapy].

OBJECTIVE: To investigate the expression and prognostic value of memory T lymphocyte in patients with non-small cell lung cancer(NSCLC) following radiotherapy. METHODS: Forty-six patients with NSCLC receiving radiotherapy in Ningbo Medical Center Lihuili Hospital from February 2010 to May 2012 were enrolled in the study and 50 healthy subjects served as the control group. The central memory T cell (TCM) and effector memory T cell (TEM) in peripheral blood CD4+, CD8+ cells were detected by flow cytometry. Survival of patients was analyzed by Kaplan-Meier curve, and the relationship between clinical features, memory T lymphocyte changes and overall survival was analyzed by multivariate Cox regression model. RESULTS: CD4+TCM, CD4+TEM, CD8+TCM levels and CD4+/CD8+ TEM of NSCLC patients were significantly lower than those of the control group, while CD4+/CD8+ TCM was significantly higher than that of the control group(all P<0.05). In NSCLC patients, CD4+TCM, CD4+TEM and CD8+TCM were decreased and CD8+TEM levels were increased 4 weeks after radiotherapy(all P<0.05); CD4+TCM, CD4+TEM and CD8+TCM at 12-week after radiotherapy were increased significantly compared with those at 4-week after radiotherapy(all P<0.05). Multivariate Cox regression analysis showed that the change of CD4+TCM after radiotherapy was correlated with the overall survival (95% CI:1.135-2.994, P<0.01). The survival rate and overall survival time for patients with decreasing CD4+ TCM were 23.1% and 10.7 months (95% CI:0.29-12.41), while those of patients with stable CD4+ TCM were 52.7% and 27.4 months (95% CI:0.00-31.26), and those of patients with increasing CD4+ TCM were 66.4% and 37.4 months (95% CI:0.33-29.21), respectively. CONCLUSIONS: NSCLC patients show a significant immunosuppression at the initial stage after radiotherapy, and then a gradual improvement. Change of memory T lymphocyte after radiotherapy can be used to help predicting the prognosis of the patients.

[c-Myc regulation of ATP-binding cassette transporter reverses chemoresistance in CD133(+) colon cancer stem cells].

The present study was aimed to explore the role of c-Myc gene regulation in maintaining the self-renewal and drug-resistant properties of colon cancer stem cells (CSCs) and the underlying mechanism. CD133(+) cells were isolated by flow cytometry cell sorting from human HT29 cancer cells. A small interfering RNA (siRNA) against c-Myc was used, and the mRNA and protein expressions of c-Myc were investigated by real-time PCR and Western blotting, respectively. To evaluate the effect of c-Myc on the drug resistance of colon CSCs, CD133(+) cells transfected with c-Myc-siRNA were exposed to 5-FU, oxaliplatin, or their combination. The expressions of ATP-binding cassette (ABC) transporters, including ABCG2, ABCB5 and MDR-1, were detected by Western blotting. The results showed that c-Myc was highly expressed in CD133(+) colon CSCs, and the protein and mRNA expressions of c-Myc were effectively blocked by c-Myc siRNA. Furthermore, CD133(+) cells showed significantly increased survival rate in chemotherapy treatment, compared with CD133(-) cells. c-Myc silencing sensitized CD133(+) cells to chemotherapy-induced cytotoxicity and down-regulated the protein expression levels of ABCG2, MDR-1 and ABCB5. These results suggest c-Myc silencing may regulate the expressions of ABC transporters in colon CSCs, and enhance the sensitivity of CSCs to the chemotherapy.