Down-regulation of RCC1 sensitizes immunotherapy by up-regulating PD-L1 via p27kip1 /CDK4 axis in non-small cell lung cancer.

In recent years, although Immune Checkpoint Inhibitors (ICIs) significantly improves survival both in local advanced stage and advanced stage of non-small cell lung cancer (NSCLC), the objective response rate of ICI monotherapy is still only about 20%. Thus, to identify the mechanisms of ICI resistance is critical to increase the efficacy of ICI treatments. By bioinformatics analysis, we found that the expression of regulator of chromosome condensation 1 (RCC1) in lung adenocarcinoma was significantly higher than that in normal lung tissue in TCGA and Oncomine databases. The survival analysis showed that high expression RCC1 was associated with the poor prognosis of NSCLC. And the expression of RCC1 was inversely related to the number of immune cell infiltration. In vitro, knockdown of RCC1 not only significantly inhibited the proliferation of lung adenocarcinoma cells but also increased the expression levels of p27kip1 and PD-L1, and decreased the expression level of CDK4 and p-Rb. In vivo, knockdown of RCC1 significantly slowed down the growth rate of tumour, and further reduced the volume and weight of tumour model after treated by PD-L1 monoclonal antibody. Therefore, RCC1 could up-regulate the expression level of PD-L1 by regulating p27kip1 /CDK4 pathway and decrease the resistance to ICIs. And this study might provide a new way to increase the efficacy of PD-L1 monoclonal antibody by inhibiting RCC1.

The Multi-Omics Analysis of Key Genes Regulating EGFR-TKI Resistance, Immune Infiltration, SCLC Transformation in EGFR-Mutant NSCLC.

BACKGROUND: Lung cancer is a high-risk malignancy worldwide. The harboring of epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) makes EGFR-tyrosine kinase inhibitor (EGFR-TKI) an attractive therapeutic option. However, patients usually suffer the primary and secondary resistance to EGFR-TKI. And the molecular alteration is still not fully clear and needs further study. METHODS: The GEO database was utilized to find the differentially expressed genes (DEGs) in NSCLC profiles resistant to the 1st or 2nd generation EGFR-TKI. We analyzed the expression and pathway enrichment of hub genes, and the prognosis of EGFR mutant/wild-type lung adenocarcinoma (LUAD). Moreover, small cell lung cancer (SCLC) and TKI-resistant profiles were used to find common DEGs, and construct miRNA regulatory network. Analysis was performed of hub genes' related immune infiltration, drug sensitivity, and methylation. Further, we analyzed hub gene expression in EGFR-mutant LUAD and paracancerous tissue by qRT-PCR. RESULTS: A total of 107 DEGs were found related to TKI resistance. Eleven hub genes were obtained after visualization, of which 5 hub genes were co-expressed in SCLC with common miRNAs. Lower expression of SPP1 (hub gene) was associated with better survival in NSCLC. The immune infiltration analysis showed more CD4+ T cells in the resistant group with high expression of SPP1. SPP1 and CD44 promoters' methylations were independent prognostic factors of LUAD. And the expression level of SPP1 related to the sensitivity of EGFR-TKIs in multiple cancer cell lines. qRT-PCR validated the higher expression of SPP1 in EGFR-mutant LUAD than in normal tissue. CONCLUSION: Our study suggested that the upregulation of SPP1 might induce resistance to the 1st and 2nd generation EGFR-TKI, and influence tumor immune infiltration, resulting in poor survival. ZEB1, SPP1, MUC1, CD44, and ESRP1 might be molecular drivers of SCLC transformation of TKI resistance.

Prognostic Prediction, Immune Microenvironment, and Drug Resistance Value of Collagen Type I Alpha 1 Chain: From Gastrointestinal Cancers to Pan-Cancer Analysis.

Background: Gastrointestinal cancers patients might experience multiple primary tumors in the digestive tract. Therefore, identifying potential biomarkers can help us better understand the underlying mechanism. From the GEO database, four profiles of gastrointestinal cancers were gathered for the screening process, and six hub genes were found by bioinformatics analysis. Collagen type I alpha 1 chain (COL1A1), one of the hub genes, is a component of the extracellular matrix and is critical for tumor microenvironment. However, the expression level, signaling pathway, prognostic prediction, and immunological value of COL1A1 in different cancers remain unclear. Methods: We comprehensively analyzed gene expression and genetic alteration patterns of COL1A1 among 33 types of malignancies from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression projects. Besides, we explored the correlation of COL1A1 with cancer prognosis, immune infiltrates, PD-L1, tumor mutational burden (TMB)/microsatellite instability status (MSI), and the pathway and drug sensitivity of co-expressed genes. Results: The results showed that COL1A1 was highly expressed and associated with poor prognosis in the majority of cancers. The most common alteration type of COL1A1 was missense mutation, and COL1A1 was associated with poor prognosis in KIRP, LGG, MESO, SKCM, and STAD. For the immunologic significance, COL1A1 expression was closely related to high TMB in THYM, LAML, ACC, KICH, PRAD, and LGG, and high MSI in TGCT, MESO, PRAD, COAD, SARC, and CESC. In addition, COL1A1 was positively correlated with the abundance of CAFs, macrophages, and tumor-infiltrating lymphocytes. However, it was negatively correlated with CD8+ T cells mainly in CESC, HNSC-HPV+, and SKCM. Besides, as a component of the extracellular matrix, COL1A1 was involved in the activation of epithelial-mesenchymal transition (EMT), and high expression of HTRA1 was resistant to multiple drugs. Conclusion: COL1A1 can serve as a prognostic and immunological biomarker in different cancers.

Efficacy and safety of apatinib treatment for gastric cancer, hepatocellular carcinoma and non-small cell lung cancer: a meta-analysis.

Apatinib (Aitan®, brand name in China) is a new anti-antiangiogenic agent that has recently been approved for the treatment of advanced gastric cancer (GC) in China. Nevertheless, its therapeutic efficacy against other types of advanced solid tumors remains unclear. This meta-analysis examines the short-term efficacy and safety of apatinib or combination therapy for GC, hepatocellular carcinoma (HCC) and non-small-cell lung cancer (NSCLC); and provides a discussion of its anti-angiogenesis therapy applications. Seven clinical studies met the inclusion criteria. The treatment of cancers using apatinib was more successful compared to therapy without apatinib. Both objective response rates (ORRs) and disease control rates (DCRs) were significantly improved in the apatinib group compared to those in the control group (RR=2.18, 95% CI 1.30-3.65; RR=2.09, 95% CI 1.21-3.60). The DCR of 850 mg qd and 750 mg qd were higher than those in the control group (P<0.05). Based on the short-term acute adverse reactions of apatinib, significant differences between groups were found for hypertension, urine protein, hand foot syndrome, and gastrointestinal reactions (diarrhea), while no significant differences were found for myelosuppression, nausea and vomiting. Moreover, the results showed that apatinib prolonged patient survival (HR=0.38, 95% CI: 0.28-0.52), and the effect was more pronounced in patients treated with 750 mg qd or 850 mg qd of apatinib than in those treated with a dose of ≤500 mg qd. Additionally, compared to its second-line application, the third-line application was shown to further reduce the risk ratio in patients. Furthermore, overall survival was longer in patients treated with apatinib. Apatinib was shown to have certain short-term effects and survival benefits on GC, HCC, and NSCLC with controllable adverse effects.