Mucosal associated invariant T (MAIT) cells are important for immune defense against infectiousMucosal associated invariant T (MAIT) cells are innate-like T cells expressing a semi-invariant T cell receptor (TCR) of Vα 7.2-Jα 33 chain and a limited array of Vβ 2 or Vβ 13 chain in humans 1 . Circulating and tissue-infiltrating MAIT cells can be characterized by expressing Vα 7.2 segment with either CD161 or IL-18Rα on cell surface 2,3 . MAIT cells are preferably resident in the intestinal mucosa and liver in humans [4][5][6] . In contrast to conventional T cells that recognize specific antigen peptides, MAIT cells can recognize and respond to microbial vitamin B metabolites in the major histocompatibility complex class I (MHC I)-related molecule (MR1) restricted manner [7][8][9][10] . Co-cultured with bacterium-infected antigen presenting cells (APC), activated MAIT cells can produce diverse cytokines, including interferon-γ (IFN-γ ), tumor necrosis factor-α (TNF-α ) and interleukin-17A (IL-17A) 3,11,12 .It was considered that MAIT cells acquired memory phenotypes after birth and accumulated in the lamina propria of intestinal mucosa in a manner depending on B cells and the commensal flora 13 . However, a recent study in the human fetus indicates that MAIT cells can acquire memory phenotypes before birth, independent of established commensal flora 14 . Previous studies have shown the importance of MAIT cells in host defense against various infectious pathogens 15-18 . Notably, accumulative MAIT cells protect from TNBS-induced colitis in rodents 19 and inflammatory bowel disease in humans 20 . Therefore, MAIT cells in the intestinal lamina propria may be natural protectors from infection and inflammation.Colorectal cancer (CRC) is one of the most common malignant tumors worldwide. The pathogenesis of CRC is attributed to epithelial genetic mutations, impaired mucosal integrity, disordered microbiota and inflammation 21 . CRC usually disrupts the mucosal homeostasis and barrier function. Its development and progression

Gastric cancer (GC) is one of the leading causes of cancer death in the world. The role of histone deacetylase 4 (HDAC4) in specific cell and tissue types has been identified. However, its biological roles in the development of gastric cancer remain largely unexplored. Quantitative real time PCR (qRT-PCR) and western blot were used to analyze the expression of HDAC4 in the clinical samples. siRNA and overexpression of HDAC4 and siRNA p21 were used to study functional effects in a proliferation, a colony formation, a adenosine 5′-triphosphate (ATP) assay and reactive oxygen species(ROS) generation, cell cycle, cell apoptosis rates, and autophagy assays. HDAC4 was up-regulated in gastric cancer tissues and several gastric cancer cell lines. The proliferation, colony formation ability and ATP level were enhanced in HDAC4 overexpression SGC-7901 cells, but inhibited in HDAC4 knockdown SGC-7901 cells. HDAC4 knockdown led to G0/G1 phase cell arrest and caused apoptosis and ROS increase. Moreover, HDAC4 was found to inhibit p21 expression in gastric cancer SGC-7901 cells. p21 knockdown dramatically attenuated cell proliferation inhibition, cell cycle arrest, cell apoptosis promotion and autophagy up-regulation in HDAC4-siRNA SGC-7901 cells. We demonstrated that HDAC4 promotes gastric cancer cell progression mediated through the repression of p21. Our results provide an experimental basis for understanding the pro-tumor mechanism of HDAC4 as treatment for gastric cancer.

Multikinase inhibitors with antiangiogenic properties used to be standard therapy for patients with advanced hepatocellular carcinoma (HCC). Recently, several antiangiogenic agents (lenvatinib, cabozantinib, and ramucirumab) have demonstrated antitumor activity for advanced HCC in randomized controlled trials. However, the landscape of drug development for HCC may change dramatically with the advent of immune checkpoint inhibitor therapy, particularly the anti–programmed cell death-1 (anti-PD1) agents. In addition, early-phase clinical trials of combination of anti–PD-1 and antiangiogenic agents have shown very promising anti-tumor activity in patients with advanced HCC. Therefore, the critical research questions at present are whether this combination strategy will be the next generation of standard therapy and which antiangiogenic agents will be the optimal partner for the combination. All of the 4 multikinase inhibitors for HCC (sorafenib, regorafenib, lenvatinib, and cabozantinib) have been reported to have immune modulatory effects. The authors systematically reviewed the pre-clinical evidence of their immune modulatory effects to explore whether these effects were mediated by angiogenesis inhibition or by other “off-target” effects on the tumor microenvironment. Studies of sorafenib comprised the majority (58 of the 71) of the research articles reviewed. Potentially beneficial effects on anti-tumor immunity may result from increased M1 polarization of macrophages and stimulation of CD8 T cell function. On the other hand, high dosage of the kinase inhibitors in pre-clinical models and hypoxia associated with angiogenesis may contribute to immune suppression in the tumor microenvironment. Sorafenib and other multikinase inhibitors may promote anti-tumor immunity through modulation of multiple immune cell types as well as the tumor microenvironment. The optimal immune modulatory dosage should be defined to facilitate design of future combination regimens.

Background The reliability of MUC2 as a prognostic marker in colorectal cancer (CRC) is controversial. This study evaluated the association between MUC2 expression levels in CRC tissues and prognosis. Methods The PubMed, Web of Science, Embase, Cochrane Library, China Biology Medicine disc (CBMdisc), Wanfang Database, and China National Knowledge Infrastructure (CNKI) databases were searched to identify studies exploring the relationship between MUC2 expression in CRC tissues and overall survival (OS). Pooled hazard ratios (HRs) and risk ratios (RRs) with 95% confidence intervals (CIs) were used to evaluate the associations between MUC2 expression levels and prognosis and MUC2 expression levels and CRC clinicopathological characteristics, respectively. Results The meta-analysis included 11 studies (2619 patients). Low MUC2 expression level was significantly associated with poor OS (HR, 1.67; 95% CI, 1.43–1.94; P < 0.00001) and disease-free survival (DFS)/recurrence-free survival (RFS) (HR, 1.60; 95% CI, 1.21–2.12; P = 0.001) in patients with CRC. Low MUC2 expression level was associated with advanced TNM stage (RR, 1.42; 95% CI, 1.26–1.60; P < 0.00001), lymph node metastasis (RR, 1.41; 95% CI, 1.25–1.60; P < 0.00001), lymphatic invasion (RR,1.64; 95% CI, 1.26–2.12; P = 0.0002), rectal tumor site (RR, 1.26; 95% CI, 1.09–1.46; P = 0.001), and large tumor size (RR,1.32; 95% CI, 1.02–1.70; P = 0.03). There were no associations between low MUC2 expression level and gender, histological grade, depth of invasion, and distant metastasis. Conclusion The low levels of MUC2 in CRC tissues are poor prognostic factor independent of stage or other well-recognized markers of later-stage disease. Large well-designed cohort studies are required to validate MUC2 as a biomarker for poor prognosis in CRC.

Background: Anti-programmed cell death-1(anti-PD1) treatment has shown promising antitumor efficacy in patients with advanced hepatocellular carcinoma (HCC). This study sought to explore the functional significance of programmed death ligand-1 (PD-L1) expression in tumor cells in the tumor microenvironment. Methods: The mouse liver cancer cell line BNL-MEA was transfected with PD-L1 plasmids and stable clones expressing PD-L1 were selected. An orthotopic HCC model was generated by implanting the cells into the subcapsular space of BALB/c mice. Cell growth features were measured by proliferation assay, colony formation, flow cytometry (in vitro), ultrasonography, and animal survival (in vivo). The changes in T-cell function were examined by cytokine assay, expression of T-cell related genes, and flow cytometry. The efficacy of anti-PD1 therapy was compared between the parental and PD-L1-expressing tumors. Results: PD-L1 expression did not affect growth characteristics of BNL-MEA cells but downregulated the expression of genes related to T-cell activation in the tumor microenvironment. Co-culture of PD-L1-expressing BNL-MEA cells with CD8+ T cells reduced T-cell proliferation and expression of cytokines IFNγ and TNFα. Tumors with PD-L1 expression showed better response to anti-PD1 therapy and depletion of CD8+ T cells abolished the antitumor effect. The difference in treatment response between parental and PD-L1-expressing tumors disappeared when a combination of anti-PD1 and sorafenib was given. Conclusions: PD-L1 expression in HCC cells may inhibit T-cell function in the liver tumor microenvironment. Anti-PD1 therapy appeared more effective in PD-L1-expressing than nonexpressing tumors, but the difference was diminished by the addition of sorafenib.

ObjectiveMonocytes and macrophages can infiltrate into tumor microenvironment and regulate the progression of tumors. This study aimed at determining the frequency of different subsets of circulating monocytes and tumor infiltrating macrophages (TIMs) in patients with colorectal cancer (CRC).MethodsThe frequency of different subsets of circulating monocytes was characterized in 46 CRC patients and 22 healthy controls (HC) by flow cytometry. The frequency of different subsets of macrophages was analyzed in TIMs from 30 tumor tissues and in lamina propria mononuclear cells (LPMCs) from 12 non-tumor tissues. The concentrations of plasma cytokines and carcinoembryonic antigen (CEA) were determined. The potential association of these measures with the values of clinical parameters was analyzed.ResultsIn comparison with that in the HC, the percentages of circulating CD14+CD169+, CD14+CD169+CD163+ and CD14+CD169+CD206+ monocytes and TIMs CD14+CD169+ as well as IL-10+CD14+CD169+, but not IL-12+ CD14+CD169+ macrophages were significantly increased, accompanied by higher levels of plasma IL-10 in the CRC patients. The percentages of CD14+CD169+ circulating monocytes and TIM macrophages were associated with the stage of disease and correlated positively with the levels of plasma IL-10 and CEA in CRC patients.ConclusionOur data suggest that an increase in the frequency of CD14+CD169+ cells may be associated with the development and progression of CRC and is concomitant rise of both, pro-tumor (M2-like, IL-10 producing) and anti-tumor (M1-like, IL-12 producing) monocytes and infiltrating macrophages. The frequency of CD14+CD169+ circulating monocytes and infiltrating macrophages may serve as a biomarker for evaluating the pathogenic degrees of CRC.

The apoptosis-stimulating protein of p53 (ASPP) family is a newly identified family protein including ASPP1, ASPP2 and inhibitor of ASPP (iASPP), by which the tumor protein 53 (TP53)-mediated apoptotic process is selectively regulated. Downregulation of ASPP1/ASPP2 and upregulation of iASPP were revealed to be associated with a poor prognosis and metastasis in several types of cancer. However, to the best of our knowledge, the expression of ASPP in colorectal cancer (CRC) has not previously been investigated. The present study analyzed ASPP expression in human CRC tissues with multiple clinical and pathological profiles. A total of 41 patients diagnosed with CRC were enrolled in the present study. The expression of ASPP was detected by immunohistochemistry, immunofluorescence and reverse transcription-quantitative polymerase chain reaction. In addition, the variation in ASPP expression was examined in a number of pathological groups. The associations among ASPP expression, and the expression of TP53, plasma carcinoembryonic antigen (CEA) levels and α-fetoprotein (AFP) levels were also investigated. ASPP1 and ASPP2 expression was significantly reduced, while iASPP expression was elevated in CRC samples compared with expression in adjacent non-cancerous tissues. Downregulation of ASPP1 was detected in the TP53-positive group compared with the TP53-negative group. The increase in iASPP expression was correlated with the grade of malignancy, but not with regional lymph node status or metastases. The expression of ASPP2 was negatively correlated with plasma CEA levels. The results of the present study, not only enrich CRC epidemic and pathological data, but also provide valuable indices for CRC clinical treatment and prognosis.

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