Chronic inflammation is thought to be a major driving force for the development of colitis-associated colorectal cancer (CAC). As one member of proinflammatory cytokine family, granulocyte macrophage colony-stimulating factor (GM-CSF) has been identified to play a key role in CAC pathogenesis recently. The underlying mechanisms, however, remain largely unknown. In this study, we found that myeloid-derived suppressor cells (MDSCs) accumulated increasingly in the lesions during the progression from colitis to cancer, which was critical for CAC formation. Importantly, this MDSC accumulation was controlled by GM-CSF. MDSC number decreased significantly in GM-CSF-deficient mice suffering from CAC induction, and transfusion of MDSCs from wild-type CAC-bearing mice into GM-CSF-deficient counterparts led to recurrence of CAC. Furthermore, the supernatants of CAC lesions or GM-CSF alone was sufficient to differentiate hematopoietic precursors into MDSCs. Addition of neutralizing anti-GM-CSF antibody impaired the MDSC-differentiating effects of the supernatants of CAC lesions. Overall, these findings shed new insights into the mechanisms of GM-CSF underlying CAC development, by inducing/recruiting CAC-promoting MDSCs. Blocking GM-CSF activity or MDSC function may represent new therapeutic strategies for CAC in clinic.

Background: The KIF5B-RET fusion gene is a novel oncogene that has been observed in a subset of lung cancers in recent years. However, the results of related epidemiological studies remain unclear. Thus, a meta-analysis was conducted to evaluate the correlation of KIF5B-RET expression based on RT-PCR detection with clinicopathological features and prognosis of lung cancer. Methods: The PubMed, Google Scholar, Wiley Online, SpringerLink and Chinese National Knowledge Infrastructure databases were searched to identify the eligible studies. The association of the occurrence of KIF5B-RET fusion gene in lung cancer with age, gender, smoking status, histology type, differentiation and TNM stage was analyzed. HR, overall survival (OS) and progression-free survival (PFS) were used to describe the prognosis of patients with lung cancer. The OR and 95% CI were calculated to assess the correlations. Random- and fixed-effects models were used to analyze the data. Results: A total of 13 studies, which included 8,859 lung cancer patients, were included in the study based on the inclusion criteria. A total of 121 patients with positive KIF5B-RET fusion gene status were detected, with a positive expression rate of 1.36%. KIF5B-RET fusion gene status was identified at significantly higher frequencies in female (OR=0.67, 95% CI=0.48–0.94) than male patients, and the same trend was found in young (<60 years) patients (OR=0.08, 95% CI=0.01–0.45) compared with old patients (≥60 years). No differences were found in the TNM stage, histology, differentiation and smoking. Based on the prognosis, no difference was found between the status of the positive and negative KIF5B-RET fusion genes in OS and PFS of patients. Conclusion: The KIF5B-RET fusion gene occurred predominantly in young female patients with lung cancer. However, the relationship between the expression of the fusion gene and the prognosis of lung patients remains unclear.

Background: Inhibitors targeting immune checkpoints, such as PD-1/PD-L1 and CTLA-4, have prolonged survival in small groups of non-small cell lung cancer (NSCLC) patients, but biomarkers predictive of the response to the immune checkpoint inhibitors (ICIs) remain rare. Methods: The nonnegative matrix factorization (NMF) was performed for TCGA-NSCLC tumor samples based on the LM22 immune signature to construct subgroups. Characterization of NMF subgroups involved the single sample gene set variation analysis (ssGSVA), and mutation/copy number alteration and methylation analyses. Construction of RNA interaction network was based on the identification of differentially expressed RNAs (DERs). The prognostic predictor was constructed by a LASSO-Cox regression model. Four GEO datasets were used for the validation analysis. Results: Four immune based NMF subgroups among NSCLC patients were identified. Genetic and epigenetic analyses between subgroups revealed an important role of somatic copy number alterations in determining the immune checkpoint expression on specific immune cells. Seven hub genes were recognized in the regulatory network closely related to the immune phenotype, and a three-gene prognosis predictor was constructed. Conclusions: Our study established an immune-based prognosis predictor, which might have the potential to select subgroups benefiting from the ICI treatment, for NSCLC patients using publicly available databases.