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Abstract Background Noninvasive and effective methods of early diagnosis of colorectal cancer (CRC) are underexplored. Inflammation is known to play an important role in the tumor microenvironment of CRC. Therefore, the aim of this study was to elucidate novel inflammatory biomarkers related to early diagnosis and prognosis of CRC. Methods Based on the results from a multiplex assay and a pan-cancer screening of TCGA data with 18 cancer types, we identified several targeted biomarkers. We further confirmed these results using a trial cohort of 112 CRC patients and 151 controls (59 healthy donors, 52 colitis and 40 colorectal adenoma patients) by Elisa and immunohistochemistry (IHC). The biomarkers expression levels in CRC patients of different clinical stages were compared. The targeted biomarkers panel was developed using logistic regression model and was then validated using an independent cohort including 75 CRC patients and 90 controls (35 healthy donors, 20 colitis and 35 colorectal adenoma patients). Diagnostic accuracy was evaluated using area under the receiver-operating characteristic (ROC) curve and overall survival analysis was used for prognosis. Gene ontology (GO) analyses and Gene set enrichment analyses (GSEA) were performed to predict the function of the candidate biomarkers. Results CCL20 and IL-17A were identified as candidate biomarkers using multiplex assay and pan-cancer screening of TCGA data. Elisa and IHC demonstrated that both CCL20 and IL-17A levels were highly expressed in CRC patients, more especially in patients with advanced stage disease. A signature expression of the two biomarkers showed high diagnostic accuracy of CRC. Importantly, the diagnostic sensitivity and specificity were still satisfactory in the early stage and low carcinoembryonic antigen (CEA) level groups. Bioinformatics analysis revealed that CCL20 and IL-17A may be involved in CRC progression. In addition, the diagnostic performance of CCL20 and IL-17A in combination was superior to that of either marker alone. Conclusions Serum CCL20 and IL-17A levels were identified as independent prognostic markers for CRC. The CCL20-IL-17A panel exhibited a good performance in the diagnosis of early stage CRC.

Abstract Lung cancer is the leading cause of cancer‐related deaths worldwide. Although several therapeutic strategies have been employed to curb lung cancer, the survival rate is still poor owing to the development of drug resistance. The mechanisms underlying drug resistance development are incompletely understood. Here, we aimed to identify the common signaling pathways involved in drug resistance in non‐small cell lung cancer (NSCLC). Three published transcriptome microarray data were downloaded from the Gene Expression Omnibus (GEO) database comprising different drug‐resistant cell lines and their parental cell lines. Differentially expressed genes (DEGs) were identified and used to perform Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. An overlapping analysis was performed for KEGG pathways enriched from all the three datasets to identify the common signaling pathways. As a result, we found that metabolic pathways, ubiquitin‐mediated proteolysis, and mitogen‐activated protein kinase (MAPK) signaling were the most aberrantly expressed signaling pathways. The knockdown of nicotinamide phosphoribosyltransferase (NAMPT), the gene involved in metabolic pathways and known to be upregulated in drug‐resistant tumor cells, was shown to increase the apoptosis of cisplatin‐resistant A549 cells following cisplatin treatment. Thus, our results provide an in‐depth analysis of the signaling pathways that are commonly altered in drug‐resistant NSCLC cell lines and highlight the potential strategy that facilitates the development of interventions to interfere with upregulated signaling pathways as well as to boost downregulated signaling pathways in drug‐resistant tumors for the elimination of multiple resistance of NSCLC.

Abstract Background Chemotherapy combined with immunotherapy becomes the main trend in lung cancer intervention; however, how chemotherapy promotes the immune function remains elusive. Therefore, we sought to determine how chemotherapy promotes the immune function. Methods We determined in 100 NSCLC patients the expression of CD8, functional markers (IFN-γ, Granzyme B, and Perforin) and specific chemokines by quantitative real-time reverse transcriptase-PCR. Functional experiments were carried out to check whether docetaxel (DOC), a chemotherapeutic agent, modifies the expression of HMGB1 and CXCL11, and influences the infiltration properties of CD8+ T cells to the tumor microenvironment. The mechanism of the release of HMGB1 and CXCL11 was determined by flow cytometry, immunofluorescence and western blotting. In in vivo experiment, we confirmed how DOC enhanced the recruitment of HER2-CAR T cells to tumor sites. Results We found that DOC upregulated the expression of chemokine receptor ligand CXCL11 in tumor microenvironment and subsequently enhanced CD8+ T cell recruitment. DOC treatment significantly increased HMGB1 release in an ROS-dependent manner. Recombinant protein HMGB1 stimulated the secretion of CXCL11 via NF-κB activation in vitro. Tumors from DOC-treated mice exhibited higher expression of HMGB1 and CXCL11, more HER2-CAR T cell infiltration, and reduced progression, relative to control. Increased HMGB1 and CXCL11 expressions were positively correlated with prolonged overall survival of lung cancer patients. Conclusions Our results demonstrate that DOC induces CD8+ T cell recruitment to the tumor microenvironment by enhancing the secretion of HMGB1 and CXCL11, thus improving the anti-tumor efficacy, indicating that modulating the HMGB1-CXCL11 axis might be helpful for NSCLC treatment.

Studies have reported a positive correlation between elevated CD8+ T cells in the tumor microenvironment (TME) and good prognosis in cancer. However, the mechanisms linking T cell tumor-infiltration and tumor rejection are yet to be fully understood. The cells and factors of the TME facilitate tumor development in various ways. CD8+ T cell function is influenced by a number of factors, including CD8+ T cell trafficking and localization into tumor sites; as well as CD8+ T cell growth and differentiation. This review highlights recent literature as well as currently evolving concepts regarding the fates of CD8+ T cells in the TME from three different aspects CD8+ T cell trafficking, differentiation and function. A thorough understanding of factors contributing to the fates of CD8+ T cells will allow researchers to develop new strategies and improve on already existing strategies to facilitate CD8+ T cell mediated anti-tumor function, impede T cell dysfunction and modulate the TME into a less immunosuppressive TME. Keywords: CD8+ T cell fates, Tumor microenvironment, CD8+ T cell differentiation, CD8+ T cell trafficking, T cell exhaustion

The expression and function of CD163 in glioma are not fully understood. In this report, we collected totally 1323 glioma samples from the Chinese Glioma Genome Atlas (CGGA) dataset, including 325 RNA-seq data and 301 mRNA microarray data, and 697 glioma samples from The Cancer Genome Atlas (TCGA) dataset to characterize the molecular and clinical features of CD163 in glioma by conducting a large-scale study. We found that CD163 expression was positively associated with the grade of malignancy of glioma. CD163 expression was up-regulated in IDH wild-type glioma and mesenchymal subtype. Gene ontology analysis suggested that CD163-related genes were more involved in immune response and angiogenesis in glioma. Moreover, CD163 showed a positive relationship with stromal and immune cell populations. Kaplan–Meier curves analysis revealed that higher CD163 expression indicated significantly poor survival in glioma and glioblastoma multiforme (GBM). Pearson correlation analysis revealed that CD163 was robustly associated with the immune checkpoints and other macrophage markers. These results demonstrated that CD163 predicts poor prognosis in glioma patients. Additionally, combination of CD163 and immune checkpoints may impair angiogenesis and reverse dysfunctional phenotypes of T cells, which suggest that CD163 may be a promising biomarker and target for immunotherapeutic strategies. Abbreviations: CGGA: Chinese Glioma Genome Atlas; TCGA: The Cancer Genome Atlas; TAMs: Tumor associated macrophages; IDH: isocitrate dehydrogenase; GBM: glioblastoma