AIMTo investigate the clinical significance of preoperative systemic immune-inflammation index (SII) in patients with colorectal cancer (CRC).METHODSA retrospective analysis of 1383 cases with CRC was performed following radical surgery. SII was calculated with the formula SII = (P × N)/L, where P, N, and L refer to peripheral platelet, neutrophil, and lymphocyte counts, respectively. The clinicopathological features and follow-up data were evaluated to compare SII with other systemic inflammation-based prognostic indices such as the neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) in patients with CRC.RESULTSThe optimal cut-off point for SII was defined as 340. The overall survival (OS) and disease-free survival (DFS) were better in patients with low NLR, PLR, and SII (P < 0.05). The SII was an independent predictor of OS and DFS in multivariate analysis. The area under the receiver-operating characteristics (ROC) curve for SII (0.707) was larger than those for NLR (0.602) and PLR (0.566). In contrast to NLR and PLR, SII could effectively discriminate between the TNM subgroups.CONCLUSIONSII is a more powerful tool for predicting survival outcome in patients with CRC. It might assist the identification of high-risk patients among patients with the same TNM stage.
The success of checkpoint inhibitors in cancer treatment is associated with the infiltration of tissue-resident memory T (Trm) cells. In this study, we found that about 30% of tumorinfiltrating lymphocytes (TIL) in the tumor microenvironment of gastric adenocarcinoma were CD69 þ CD103 þ Trm cells. Trm cells were low in patients with metastasis, and the presence of Trm cells was associated with better prognosis in patients with gastric adenocarcinoma. Trm cells expressed high PD-1, TIGIT, and CD39 and represented tumor-reactive TILs. Instead of utilizing glucose, Trm cells relied on fatty acid oxidation for cell survival. Deprivation of fatty acid resulted in Trm cell death. In a tumor cell-T-cell coculture system, gastric adenocarcinoma cells outcompeted Trm cells for lipid uptake and induced Trm cell death. Targeting PD-L1 decreased fatty acid binding protein (Fabp) 4 and Fabp5 expression in tumor cells of gastric adenocarcinoma. In contrast, the blockade of PD-L1 increased Fabp4/5 expression in Trm cells, promoting lipid uptake by Trm cells and resulting in better survival of Trm cells in vitro and in vivo. PD-L1 blockade unleashed Trm cells specifically in the patientderived xenograft (PDX) mice. PDX mice that did not respond to PD-L1 blockade had less Trm cells than responders. Together, these data demonstrated that Trm cells represent a subset of TILs in the antitumor immune response and that metabolic reprogramming could be a promising way to prolong the longevity of Trm cells and enhance antitumor immunity in gastric adenocarcinoma.
Terpenoids represent the largest family of natural products. Their structural diversity is largely due to variable skeletons generated by terpene synthases. However, terpene skeletons found in nature are much more than those generated from known terpene synthases. Most promiscuous terpene synthases (i.e. those that can generate more than one product) have not been comprehensively characterised. Here, we first demonstrated that the promiscuous terpene synthases can produce more variable terpenoids in vivo by converting precursor polyisoprenoid diphosphates of different lengths (C, C, C, C). To release the synthetic potential of these enzymes, we integrated the engineered MVA pathway, combinatorial biosynthesis, and point mutagenesis to depict the comprehensive product profiles. In total, eight new terpenoids were characterised by NMR and three new skeletons were revealed. This work highlights the key role of metabolic engineering for natural product discovery.
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