A GAPDH serotonylation system couples CD8+ T cell glycolytic metabolism to antitumor immunity.

Apart from the canonical serotonin (5-hydroxytryptamine [5-HT])-receptor signaling transduction pattern, 5-HT-involved post-translational serotonylation has recently been noted. Here, we report a glyceraldehyde-3-phosphate dehydrogenase (GAPDH) serotonylation system that promotes the glycolytic metabolism and antitumor immune activity of CD8+ T cells. Tissue transglutaminase 2 (TGM2) transfers 5-HT to GAPDH glutamine 262 and catalyzes the serotonylation reaction. Serotonylation supports the cytoplasmic localization of GAPDH, which induces a glycolytic metabolic shift in CD8+ T cells and contributes to antitumor immunity. CD8+ T cells accumulate intracellular 5-HT for serotonylation through both synthesis by tryptophan hydroxylase 1 (TPH1) and uptake from the extracellular compartment via serotonin transporter (SERT). Monoamine oxidase A (MAOA) degrades 5-HT and acts as an intrinsic negative regulator of CD8+ T cells. The adoptive transfer of 5-HT-producing TPH1-overexpressing chimeric antigen receptor T (CAR-T) cells induced a robust antitumor response. Our findings expand the known range of neuroimmune interaction patterns by providing evidence of receptor-independent serotonylation post-translational modification.

A proposed modification for the Barcelona Clinic Liver Cancer staging system: Adding bile duct tumor thrombus status in patients with hepatocellular carcinoma.

BACKGROUND: The Barcelona Clinic Liver Cancer (BCLC) staging system is widely applied to stage hepatocellular carcinoma (HCC). However, it may be inaccurate when applied to East Asian HCC patients. In this study, a large Chinese HCC cohort was analyzed to evaluate possible modifications for the BCLC staging system. METHODS: Between January 1995 and December 2009, 622 HCC patients who underwent hepatectomy were enrolled. Prognostic risk factors were analyzed using univariate and multivariate analyses. The ability of the modified system to predict survival was evaluated by determining the area under the receiver operating characteristic curve. RESULTS: Patients without bile duct tumor thrombus (BDTT; 1-, 3- and 5-year overall survival, 80%, 60% and 48%, respectively) showed a substantial survival advantage over those with BDTT (1-, 3- and 5-year overall survival, 77%, 42% and 23%, respectively; χ2 = 6.280, P = 0.012). In BCLC stage 0-A patients, significant differences were identified between the BDTT group and the non-BDTT group, while no such differences were found in BCLC stage B patients. Based on this finding, BCLC stage 0-A BDTT patients were recategorized into stage B. The modified BCLC classification featured better performance in the prediction of overall survival than the original system (modified BCLC χ2 = 53.596, P < 0.001; original BCLC χ2 = 46.335, P < 0.001). The ability to predict mortality was also slightly higher using the modified BCLC system. CONCLUSIONS: Modification of the BCLC system to include BDTT status might further enhance its prognostic ability.