Heterogeneity-induced NGF-NGFR communication inefficiency promotes mitotic spindle disorganization in exhausted T cells through PREX1 suppression to impair the anti-tumor immunotherapy with PD-1 mAb in hepatocellular carcinoma.

BACKGROUND: The mechanism of decreased T cells infiltrating tumor tissues in hepatocellular carcinoma is poorly understood. METHODS: Cells were separated from the single-cell RNA-sequence dataset of hepatocellular carcinoma patients (GSE149614) for cell-cell communication. Flow cytometry, EDU staining, H3-Ser28 staining, confocal immunofluorescence staining, western blotting and naked microsubcutaneous tumors were performed for the mechanism of NGF-NGFR promoting proliferation. RESULTS: The present study has revealed that during the process of T-cell infiltration from adjacent tissues to tumor tissues, an inefficiency in NGF-NGFR communication occurs in the tumor tissues. Importantly, NGF secreted by tumor cells interacts with NGFR present on the membranes of the infiltrated T cells, thereby promoting the proliferation through the activation of mitotic spindle signals. Mechanistically, the mediation of mitotic spindle signal activation promoting proliferation is executed by HDAC1-mediated inhibition of unclear trans-localization of PREX1. Furthermore, PD-1 mAb acts synergistically with the NGF-NGFR communication to suppress tumor progression in both mouse models and HCC patients. Additionally, NGF-NGFR communication was positively correlates with the PD-1/PDL-1 expression. However, expressions of NGF and NGFR are low in tumor tissues, which is responsible for the invasive clinicopathological features and the disappointing prognosis in HCC patients. CONCLUSION: Inefficiency in NGF-NGFR communication impairs PD-1 mAb immunotherapy and could thus be utilized as a novel therapeutic target in the treatment of HCC patients in clinical practice.

IL-17A functions and the therapeutic use of IL-17A and IL-17RA targeted antibodies for cancer treatment.

Interleukin 17A (IL-17A) is a major member of the IL-17 cytokine family and is produced mainly by T helper 17 (Th17) cells. Other cells such as CD8+ T cells, γδ T cells, natural killer T cells and innate lymphoid-like cells can also produce IL-17A. In healthy individuals, IL-17A has a host-protective capacity, but excessive elevation of IL-17A is associated with the development of autoimmune diseases and cancer. Monoclonal antibodies (mAbs) targeting IL-17A (e.g., ixekizumab and secukinumab) or IL-17A receptor (IL-17RA) (e.g., brodalumab) would be investigated as potential treatments for these diseases. Currently, the application of IL-17A-targeted drugs in autoimmune diseases will provide new ideas for the treatment of tumors, and its combined application with immune checkpoint inhibitors has become a research hotspot. This article reviews the mechanism of action of IL-17A and the application of anti-IL-17A antibodies, focusing on the research progress on the mechanism of action and therapeutic blockade of IL-17A in various tumors such as colorectal cancer (CRC), lung cancer, gastric cancer and breast cancer. Moreover, we also include the results of therapeutic blockade in the field of cancer as well as recent advances in the regulation of IL-17A signaling.

FOXM1 augments sorafenib resistance and promotes progression of hepatocellular carcinoma by epigenetically activating KIF23 expression.

Sorafenib has been used to enhance the survival outcome of hepatocellular carcinoma (HCC) patients. But, occurrence resistance to sorafenib subtracts from its therapeutic benefits. Herein, we identified that FOXM1 was markedly upregulated in both tumor samples and sorafenib-resistant HCC tissues. We also demonstrated that patients with decreased FOXM1 expression had longer overall survival (OS) and progression-free survival (PFS) in the cohort of sorafenib-treated patients. For HCC cells resistant to sorafenib, the IC50 value of sorafenib and the expression of FOXM1 were increased. In addition, Downregulation of FOXM1 expression alleviated the occurrence of resistance to sorafenib and reduced the proliferative potential and viability of HCC cells. Mechanically, the suppression of the FOXM1 gene resulted in the downregulation of KIF23 levels. Moreover, downregulation of FOXM1 expression reduced the levels of RNA polymerase II (RNA pol II) and histone H3 lysine 27 acetylation (H3K27ac) on the KIF23 promoter, further epigenetically silencing the production of KIF23. More intriguingly, our results similarly revealed that FDI-6, a specific inhibitor of FOXM1, suppressed the proliferation of HCC cells resistant to sorafenib, as well as upregulation of FOXM1 or KIF23 abolished this effect. In addition, we found that FDI-6 combined with sorafenib significantly improved the therapeutic effect of sorafenib. Collectively, the present results revealed that FOXM augments sorafenib resistance and enhances HCC progression by upregulating KIF23 expression via an epigenetic mechanism, and targeting FOXM1 can be an effective treatment for HCC.

Curcumin Alleviates Hepatic Ischemia-Reperfusion Injury by Inhibiting Neutrophil Extracellular Traps Formation.

BACKGROUND: Hepatic ischemia-reperfusion injury (IRI) is a common innate immune-mediated sterile inflammatory response in liver transplantation and liver tumor resection. Neutrophil extracellular traps (NETs) can aggravate liver injury and activates innate immune response in the process of liver IRI. However, Curcumin (Cur) can reverse this damage and reduce NETs formation. Nevertheless, the specific regulatory mechanism is still unclear in liver IRI. This study aimed to explore the potential mechanisms that how does Cur alleviate hepatic IRI by inhibits NETs production and develop novel treatment regimens. METHODS: We established a hepatic IRI model by subjecting C57BL/6J mice to 60 min of ischemia, followed by reperfusion for 2 h, 6 h, 12 h, and 24 h respectively. Subsequently, we were separated into 5 groups, namely the I/R group, Cur group, DNase-1 group, Cur + DNase1 group and sham operation group. Serum alanine aminotransferase (ALT) and aspartate transaminase (AST), Hematoxylin-eosin staining, immunofluorescence, and TUNEL analysis were applied to assess liver injury degree and NETs levels. Western blot assay was used to detect the protein levels of apoptosis-related proteins and MEK pathway proteins. RESULTS: Cur could alleviate hepatic IRI by inhibiting the generation of NETs via suppressing the MEK/ERK pathway. In addition, this study also revealed that DNase-1 is vital for alleviating hepatic IRI by reducing the generation of NETs. CONCLUSIONS: Cur combined with DNase-1 was more effective than the two drugs administered alone in alleviating hepatic IRI by inhibiting the generation of NETs. These results also suggested that curcumin combined with DNase-1 was a potential therapeutic strategy to mitigate hepatic IRI.

Is dynamic contrast enhancement still necessary in multiparametric magnetic resonance for diagnosis of prostate cancer: a systematic review and meta-analysis.

BACKGROUND: The purpose of this study is to systematically review the literatures assessing the value of dynamic contrast enhancement (DCE) in the multiparametric magnetic resonance imaging (mpMRI) for the diagnosis of prostate cancer (PCa). METHODS: We searched Embase, PubMed and Web of science until January 2019 to extract articles exploring the possibilities whether the pre-biopsy biparametric magnetic resonance imaging (bpMRI) can replace the position of mpMRI in the diagnosis of PCa. The sensitivity and specificity of bpMRI were all included. The study quality was assessed by QUADAS-2. Bivariate random effects meta-analyses and a hierarchical summary receiver operating characteristic plot were performed for further study through Revman 5 and Stata12. RESULTS: After searching, we acquired 752 articles among which 45 studies with 5,217 participants were eligible for inclusion. The positive likelihood ratio for the detection of PCa was 2.40 (95% CI: 1.50-3.80) and the negative likelihood ratio was 0.31 (95% CI: 0.18-0.53). The sensitivity and specificity were 0.77 (95% CI: 0.73-0.81) and 0.81 (95% CI: 0.76-0.85) respectively. Based on our result, pooled specificity demonstrated little difference between bpMRI and mpMRI [bpMRI, 0.81 (95% CI, 0.76-0.85); mpMRI, 0.82 (95% CI, 0.72-0.88); P=0.169]. The sensitivity, however, indicated a significant difference between these two groups [bpMRI, 0.77 (95% CI, 0.73-0.81); mpMRI, 0.84 (95% CI, 0.78-0.89); P=0.001]. CONCLUSIONS: bpMRI with high b-value is a sensitive tool for diagnosing PCa. Consistent results were found in multiple subgroup analysis.