RESUMO
BACKGROUND: We evaluated the relevance of PD-1+CD8+ T-cells in gastric cancer (GC) including prognostic significance, association with chemotherapy and immunotherapy sensitivity and correlations with the tumor microenvironment (TME). METHODS: Discovery cohort: GC samples were evaluated for AE1/3, CD8, PD-1, Ki-67 and Granzyme-B expression with fluorescence-based multiplex immunohistochemistry (mIHC). Validation cohorts: we analyzed bulk RNAseq GC datasets from TCGA, the "3G" chemotherapy trial and an immunotherapy phase 2 trial. The cox proportional hazards model was used to identify factors that influenced overall survival (OS). To study the TME, we analyzed single-cell RNAseq performed on GCs. RESULTS: In the discovery cohort of 350 GCs, increased PD-1 expression of CD8 T-cells was prognostic for OS (HR 0.822, p = 0.042). PD-1 expression in CD8 T-cells highly correlated with cytolytic [Granzyme-B+] (r = 0.714, p < 0.001) and proliferative [Ki-67+] (r = 0.798, p < 0.001) activity. Analysis of bulk RNAseq datasets showed tumors with high PD-1 and CD8A expression levels had improved OS when treated with immunotherapy (HR 0.117, p = 0.036) and chemotherapy (HR 0.475, p = 0.017). Analysis of an scRNAseq dataset of 152,423 cells from 40 GCs revealed that T-cell and NK-cell proportions were higher (24% vs 18% and 19% vs 15%, p < 0.0001), while macrophage proportions were lower (7% vs 11%, p < 0.0001) in CD8PD-1high compared to CD8PD-1low tumors. CONCLUSION: This is one of the largest GC cohorts of mIHC combined with analysis of multiple datasets providing orthogonal validation of the clinical relevance of PD-1+CD8+ T-cells being associated with improved OS. CD8PD-1high tumors have distinct features of an immunologically active, T-cell inflamed TME.
Assuntos
Linfócitos T CD8-Positivos , Neoplasias Gástricas , Humanos , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Granzimas/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/terapia , Neoplasias Gástricas/metabolismo , Relevância Clínica , Antígeno Ki-67/metabolismo , Linfócitos do Interstício Tumoral/patologia , Prognóstico , Microambiente Tumoral , Antígeno B7-H1/metabolismoRESUMO
<p><b>INTRODUCTION</b>Outcomes of bariatric surgery for super obese Asians are not well reported. We aimed to compare short-term outcomes of laparoscopic sleeve gastrectomy (LSG) in Asian patients with body mass index (BMI) <47.5 kg/m to those with BMI •••••• ≥47.5 kg/m.</p><p><b>MATERIALS AND METHODS</b>A total of 272 patients from Singapore university hospital who underwent LSG from 2008 to 2015 with a follow-up of at least 6 months were included in the study. Primary endpoint was weight loss at 1-year and 3-years. Morbid obesity (Group 1, G1) was defined as BMI <47.5 kg/m and super obesity (Group2, G2) was defined as BMI ≥47.5 kg/m.</p><p><b>RESULTS</b>There were 215 patients in G1 and 57 patients in G2 (mean preoperative weight: 107.3 kg and 146.8 kg; mean follow-up: 27.9 and 26.8 months, respectively). Mean total weight loss at 3-year of 41.9 kg for G2 was significantly higher ( = 0.003) than 27.2 kg for G1. Mean percentage excess weight loss (EWL) did not differ at 3-years. There was no difference in operating time, blood loss, length of stay, 30-day morbidity and readmission. There were no conversions and mortality in both groups. Remission of herpertension ( - 0.001) and dyslipidaemia ( = 0.038) were significantly associated with achieving EWL percentage (%EWL) >50 in G1.</p><p><b>CONCLUSION</b>LSG is an equally safe and effective operation in Asians with BMI ≥47.5 kg/m2 when compare to patients with BMI <47.5 kg/m in achieving significant weight loss and improvement in comorbidities. Super obese lose more weight but have lower %EWL.</p>