No abstract

BackgroundImmune checkpoint inhibitors (ICIs), including anti-PD-1 therapy, have limited efficacy in patients with microsatellite stable (MSS) colorectal cancer (CRC). Interleukin 17A (IL-17A) activity leads to a protumor microenvironment, dependent on its ability to induce the production of inflammatory mediators, mobilize myeloid cells and reshape the tumor environment. In the present study, we aimed to investigate the role of IL-17A in resistance to antitumor immunity and to explore the feasibility of anti-IL-17A combined with anti-PD-1 therapy in MSS CRC murine models.MethodsThe expression of programmed cell death-ligand 1 (PD-L1) and its regulation by miR-15b-5p were investigated in MSS CRC cell lines and tissues. The effects of miR-15b-5p on tumorigenesis and anti-PD-1 treatment sensitivity were verified both in vitro and in colitis-associated cancer (CAC) and APCmin/+ murine models. In vivo efficacy and mechanistic studies were conducted using antibodies targeting IL-17A and PD-1 in mice bearing subcutaneous CT26 and MC38 tumors.ResultsEvaluation of clinical pathological specimens confirmed that PD-L1 mRNA levels are associated with CD8+ T cell infiltration and better prognosis. miR-15b-5p was found to downregulate the expression of PD-L1 at the protein level, inhibit tumorigenesis and enhance anti-PD-1 sensitivity in CAC and APCmin/+ CRC models. IL-17A led to high PD-L1 expression in CRC cells through regulating the P65/NRF1/miR-15b-5p axis. Combined IL-17A and PD-1 blockade had efficacy in CT26 and MC38 tumors, with more cytotoxic T lymphocytes cells and fewer myeloid-derived suppressor cells in tumors.ConclusionsIL-17A increases PD-L1 expression through the p65/NRF1/miR-15b-5p axis and promotes resistance to anti-PD-1 therapy. Blocking IL-17A improved the efficacy of anti-PD-1 therapy in MSS CRC murine models. IL-17A might serve as a therapeutic target to sensitize patients with MSS CRC to ICI therapy.

No abstract

PurposeColon cancer (CC) is a serious disease burden. The prognosis of patients with CC is different, so looking for effective biomarkers to predict prognosis is vitally important. Ferroptosis is a promising therapeutic and diagnosis strategy in CC. However, the role of ferroptosis in prognosis of CC has not been studied. The aim of the study is to build a prognosis model related ferroptosis, and provide clues for further therapy of CC.MethodsThe RNA-seq data were from TCGA (training group) and GEO (testing group). The R language and Perl language were used to process and analyze data. LASSO regression analysis was used to build the prognosis model. ssGSEA was used to compare the immune status between two groups. Immunohistochemistry was used to detect expression of AKR1C1 and CARS1 in colon cancer tissues and adjacent tissues.ResultsThe prognosis model consisted of five ferroptosis related genes (AKR1C1, ALOX12, FDFT1, ATP5MC3, and CARS1). The area under curve (AUC) at 1-, 2-, and 3-year were 0.668, 0.678, and 0.686, respectively. The high- and low-risk patients had significant survival probability and could be clearly distinguished by the PCA and t-SNE analysis. The multivariate cox regression analysis also showed the riskscore is an independent prognosis factor. Importantly, we found that the immune status between high- and low-risk patients were different obviously, such as CD8+T cells. And STING, a new promising immune target, was also correlated to our signature genes statistically significantly.ConclusionOur ferroptosis prognosis signature could predict survival of CC patients to a certain degree. And the crosstalk between ferroptosis and immune, especially STING need further studies.

It has been revealed that 2'3'-cyclic-GMP-AMP (cGAMP), a second messenger that activates the antiviral stimulator of interferon genes (STING), elicits an antitumoral immune response. Since cGAMP cannot cross the cell membrane, it is not clear how intracellular STING has been activated by extracellular cGAMP until SLC19A1 was identified as an importer to transport extracellular cGAMP into cytosol. However, SLC19A1 deficient cells also sense extracellular cGAMP, suggesting the presence of mechanisms other than the facilitating transporters for STING sensing extracellular cGAMP. Here, we identified an alternatively spliced STING isoform (plasmatic membrane STING, pmSTING) that localized in the plasma membrane with its Cterminus outside the cell, due to lack of one transmembrane domain in its N-terminus compared to canonical STING, by using immunoprecipitation, immunofluorescence and flow cytometry. Further studies showed that extracellular cGAMP not only promoted the dimerization of pmSTING and interaction of pmSTING with Tankbinding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3), but also enhanced the phosphorylation of TBK1 and IRF3 and production of interferon in pmSTING transfected cells. Additionally, we also identified similar pmSTING isoforms in other species including human. This study suggests a conserved role for pmSTING in sensing extracellular cGAMP and provides insight into cGAMP's role as an immunotransmitter.

Autologous fat transplantation (AFT) is a common and important operation in plastic surgery for soft tissue defects and adipose tissue-derived stem cells (ADSCs) are considered as a promising supplement to decrease absorption and subsequent side effects due to the ability of multiple differentiation and production of vascular endothelial growth factor (VEGF). The capacities of ADSCs can be further enhanced by treatment with 17-β estradiol (E2). Therefore, we hypothesized that E2 may promote the potential of ADSCs for AFT. In this study, ADSCs were extracted from three female patients by liposuction. In vitro studies showed that E2 supplementation at an optimal concentration of 10 -8 M resulted in enhanced proliferation, VEGF production, and adipogenic differentiation of human ADSCs, and reduced apoptosis rate in a serum-free environment. In addition, a nude mice model of fat transplantation was utilized to demonstrate the efficacy of ADSC for survival ratio in vivo. These results using the volume of fat tissues after 12 weeks compared original volume, revealed that the addition of E2-treated ADSCs induced a significantly higher tissue survival ratio (76.9 ± 1.9%) when compared with the ADSC-free system (55.5 ± 1.5%). Furthermore, increased capillary formation stained with hematoxylin-eosin (H&E) was observed in ADSCs systems after treatment with E2. Therefore, this study demonstrated E2 could promote the capacities of ADSCs about aspects of adipogenic differentiation, growth factor secretion and apoptosis reduction in vitro, vascularization improvement in vivo, and then enhanced the survival ratio of AFT.

BACKGROUND There is a close relationship between cirrhosis and hepatocellular carcinoma (HCC). Transjugular intrahepatic portosystemic shunt (TIPS) has good clinical effect in treating the complication of portal hypertension. However, because of the risk of postoperative liver failure, severe complications, and low survival rate for HCC, TIPS is contraindicated in patients with portal hypertension and liver cancer. We studied a large cohort of patients with cirrhosis and HCC who underwent TIPS for recurrent variceal bleeding and/or ascites. AIM To assess the safety, efficacy, and survival rate in patients with HCC who underwent TIPS. METHODS Group A comprised 217 patients with HCC and portal hypertension who underwent the TIPS procedure between 1999 and 2014. After TIPS deployment, these patients received palliative treatment for HCC. Group B comprised a cohort of 136 HCC patients with portal hypertension who did not undergo TIPS placement. Group B received palliative treatment for HCC plus medical therapy for portal hypertension. The clinical outcomes and survival rate were assessed. RESULTS In Group A, the primary technical success rate was 97.69% for TIPS placement, and no severe procedure-related complications of TIPS placement were reported. The control of variceal bleeding (VB) within 1 mo did not differ significantly between the groups ( P = 0.261). Absorption of refractory ascites within 1 mo, recurrence of VB, and recurrence of refractory ascites differed significantly between the groups ( P = 0.017, 0.023, and 0.009, respectively). By comparison, the rate of hepatic encephalopathy in Group B was lower than that in Group A ( P = 0.036). The 1-, 2-, 3-, 4-, and 5-year survival rates were significantly different between Groups A and B (χ 2 = 12.227, P = 0.018; χ 2 = 12.457, P = 0.014; χ 2 = 26.490, P = 0.013; χ 2 = 21.956, P = 0.009, and χ 2 = 24.596, P = 0.006, respectively). The mean survival time was 43.7 mo in Group A and 31.8 mo in Group B. Median survival time was 50.0 mo in Group A and 33.0 mo in Group B. Mean and median survival differed significantly between the two groups ( P = 0.000, χ 2 = 35.605, log-rank test). The mortality rate from VB in Group A was low than that in Group B ( P = 0.006), but the rates of hepatic tumor, hepatic failure, and multiorgan failure did not differ significantly between the two groups ( P = 0.173, 0.246 and 0.257, respectively). CONCLUSION TIPS combined with palliative treatment is saf...

No abstract