Ruiting Ye1, Han Zeng2, Zhaopei Liu2, Kaifeng Jin2, Chunnan Liu2, Sen Yan2, Yanze Yu2, Runze You2, Hongyi Zhang2, Yuan Chang3, Yiwei Wang4, Li Liu5, Yu Zhu1, Jiejie Xu6, Le Xu7, Zewei Wang8. 1. Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. 2. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. 3. Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. changyuan0802@163.com. 4. Department of Urology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 5. Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. 6. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. jjxufdu@fudan.edu.cn. 7. Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. xl11887@rjh.com.cn. 8. Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. zwwang12@fudan.edu.cn.
Abstract
BACKGROUND: Latency-associated peptide (LAP) was identified as crucial immune regulator in tumor microenvironment (TME) in recent researches. In this study, we aimed to estimate the predictive value of LAP expression for clinical survival and therapeutic response in muscle-invasive bladder cancer (MIBC). METHODS: Our study encompassed 140 MIBC patients from Zhongshan Hospital (ZSHS cohort), 401 patients from The Cancer Genome Atlas (TCGA cohort) and 195 patients received PDL1 blockade from IMvigor210 trial. Survival analyses were conducted through Kaplan-Meier curve and Cox regression model. LAP expression and its association with immune contexture were evaluated in ZSHS and TCGA cohort. RESULTS: We found that high intratumoral LAP+ cells infiltration anticipated inferior survival and adjuvant chemotherapy (ACT) response, and was closely related to an immunoevasive contexture with increased M2 macrophages, neutrophils and conspicuously a cluster of highly exhausted CD8+ T cells. The combinational analysis of LAP+ cells and CD8+ T cells infiltration stratified patients into distinct risk groups with implications for therapeutic sensitivity to PDL1 blockade and refinement of molecular classification in MIBC. CONCLUSIONS: LAP expression was correlated with patients' inferior prognosis, ACT-tolerance and an immunoevasive TME with exhausted CD8+ T cell infiltration, suggesting that LAP could serve as a promising therapeutic target in MIBC. Simultaneously, our novel TME classification based on LAP+ cells and CD8+ T cells infiltration and its potential in appraising PDL1 blockade application for MIBC patients deserved further validation.
BACKGROUND: Latency-associated peptide (LAP) was identified as crucial immune regulator in tumor microenvironment (TME) in recent researches. In this study, we aimed to estimate the predictive value of LAP expression for clinical survival and therapeutic response in muscle-invasive bladder cancer (MIBC). METHODS: Our study encompassed 140 MIBC patients from Zhongshan Hospital (ZSHS cohort), 401 patients from The Cancer Genome Atlas (TCGA cohort) and 195 patients received PDL1 blockade from IMvigor210 trial. Survival analyses were conducted through Kaplan-Meier curve and Cox regression model. LAP expression and its association with immune contexture were evaluated in ZSHS and TCGA cohort. RESULTS: We found that high intratumoral LAP+ cells infiltration anticipated inferior survival and adjuvant chemotherapy (ACT) response, and was closely related to an immunoevasive contexture with increased M2 macrophages, neutrophils and conspicuously a cluster of highly exhausted CD8+ T cells. The combinational analysis of LAP+ cells and CD8+ T cells infiltration stratified patients into distinct risk groups with implications for therapeutic sensitivity to PDL1 blockade and refinement of molecular classification in MIBC. CONCLUSIONS: LAP expression was correlated with patients' inferior prognosis, ACT-tolerance and an immunoevasive TME with exhausted CD8+ T cell infiltration, suggesting that LAP could serve as a promising therapeutic target in MIBC. Simultaneously, our novel TME classification based on LAP+ cells and CD8+ T cells infiltration and its potential in appraising PDL1 blockade application for MIBC patients deserved further validation.
Authors: H von der Maase; S W Hansen; J T Roberts; L Dogliotti; T Oliver; M J Moore; I Bodrogi; P Albers; A Knuth; C M Lippert; P Kerbrat; P Sanchez Rovira; P Wersall; S P Cleall; D F Roychowdhury; I Tomlin; C M Visseren-Grul; P F Conte Journal: J Clin Oncol Date: 2000-09 Impact factor: 44.544
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Authors: J Alfred Witjes; Harman Max Bruins; Richard Cathomas; Eva M Compérat; Nigel C Cowan; Georgios Gakis; Virginia Hernández; Estefania Linares Espinós; Anja Lorch; Yann Neuzillet; Mathieu Rouanne; George N Thalmann; Erik Veskimäe; Maria J Ribal; Antoine G van der Heijden Journal: Eur Urol Date: 2020-04-29 Impact factor: 20.096