ΔNp63-restricted viral mimicry response impedes cancer cell viability and remodels tumor microenvironment in esophageal squamous cell carcinoma.

Tumor protein p63 isoform ΔNp63 plays roles in the squamous epithelium and squamous cell carcinomas (SCCs), including esophageal SCC (ESCC). By integrating data from cell lines and our latest patient-derived organoid cultures, derived xenograft models, and clinical sample transcriptomic analyses, we identified a novel and robust oncogenic role of ΔNp63 in ESCC. We showed that ΔNp63 maintains the repression of cancer cell endogenous retrotransposon expression and cellular double-stranded RNA sensing. These subsequently lead to a restricted cancer cell viral mimicry response and suppressed induction of tumor-suppressive type I interferon (IFN-I) signaling through the regulations of Signal transducer and activator of transcription 1, Interferon regulatory factor 1, and cGAS-STING pathway. The cancer cell ΔNp63/IFN-I signaling axis affects both the cancer cell and tumor-infiltrating immune cell (TIIC) compartments. In cancer cells, depletion of ΔNp63 resulted in reduced cell viability. ΔNp63 expression is negatively associated with the anticancer responses to viral mimicry booster treatments targeting cancer cells. In the tumor microenvironment, cancer cell TP63 expression negatively correlates with multiple TIIC signatures in ESCC clinical samples. ΔNp63 depletion leads to increased cancer cell antigen presentation molecule expression and enhanced recruitment and reprogramming of tumor-infiltrating myeloid cells. Similar IFN-I signaling and TIIC signature association with ΔNp63 were also observed in lung SCC. These results support the potential application of ΔNp63 as a therapeutic target and a biomarker to guide candidate anticancer treatments exploring viral mimicry responses.

Five-year effectiveness of bariatric surgery on disease remission, weight loss, and changes of metabolic parameters in obese patients with type 2 diabetes: A population-based propensity score-matched cohort study.

AIMS: To compare disease remission rates, weight loss, and changes of metabolic parameters of patients after bariatric surgery with nonsurgical patients. METHODS: Based on the 2006-2017 Hospital Authority database, a population-based retrospective cohort of obese type 2 diabetes mellitus (T2DM) patients with and without bariatric surgery were identified. Surgical patients were matched with nonsurgical patients on 1-to-5 propensity score. Remission rates of diabetes, hypertension, and dyslipidaemia were reported annually up to 60 months. Changes in weight loss measurements (Body Mass Index [BMI], percentage of total weight loss [%TWL], percentage of excess weight loss [%EWL], and percentage of rebound in excess weight loss [%REWL]) and metabolic parameters (haemoglobin A1c [HbA1c ], systolic blood pressure [SBP], diastolic blood pressure [DBP], and low-density lipoprotein cholesterol [LDL-C]) were measured for both groups. RESULTS: Four hundred one surgical patients (310 restrictive surgeries; 91 bypass surgeries) and 1894 nonsurgical patients were included. Surgical patients had higher remission rates in diabetes and dyslipidaemia and better glycaemic control at 12 to 60 months (all Ps < .01). SBP and DBP were significantly lower for surgical group up to 12 months and similar between two groups after 12 months. Surgical patients had significantly lower BMI during follow-up period. %TWL and %EWL were higher in the surgery group (15.7% vs 3.7%; 48.8% vs 12.0%) at 60 months (P < .001); differences in %REWL between two groups were insignificant. The effectiveness of restrictive and bypass surgeries was similar at 60 months, although restrictive surgeries were slightly more effective in T2DM remission. CONCLUSIONS: Bariatric surgery was effective in weight loss, remission of diabetes, and dyslipidaemia in 5-year post-surgery.