Jianhua Liu1,2, Hao Chen3, Guibin Qiao4, Jia-Tao Zhang5, Shuaitong Zhang6,7, Changbin Zhu8, Yu Chen9, Jiming Tang4, Weiwei Li8, Siyun Wang10, Hongxia Tian5, Zhihong Chen5, Dong Ma11, Jie Tian12,13, Yi-Long Wu14,15. 1. The Second School of Clinical Medicine, Southern Medical University, 253 Gongye Middle Avenue, Guangzhou, 510280, China. 2. Department of Oncology, Cancer Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, No.123 Huifu Road West, Guangzhou, 510180, China. 3. Department of Gastroenterology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China. 4. Department of Thoracic Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China. 5. Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China. 6. School of Engineering Medicine, Beihang University, No.37 Xueyuan Road, Haidian District, Beijing, 100191, China. 7. CAS Key Laboratory of Molecular Imaging, Institute of Automation,, Chinese Academy of Sciences, Beijing, 100190, China. 8. Department of Translational Medicine, Amoy Diagnostics Co., Ltd, Xiamen, 361027, China. 9. Department of Pathology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China. 10. Department of PET Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China. 11. Department of Oncology, Cancer Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, No.123 Huifu Road West, Guangzhou, 510180, China. dr_madong@163.com. 12. School of Engineering Medicine, Beihang University, No.37 Xueyuan Road, Haidian District, Beijing, 100191, China. jie.tian@ia.ac.cn. 13. CAS Key Laboratory of Molecular Imaging, Institute of Automation,, Chinese Academy of Sciences, Beijing, 100190, China. jie.tian@ia.ac.cn. 14. The Second School of Clinical Medicine, Southern Medical University, 253 Gongye Middle Avenue, Guangzhou, 510280, China. syylwu@live.cn. 15. Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China. syylwu@live.cn.
Abstract
BACKGROUND: Immunotherapy has largely improved clinical outcome of patients with esophageal squamous cell carcinoma (ESCC). However, a proportion of patients still fail to benefit. Thus, biomarkers predicting therapeutic resistance and underlying mechanism needs to be investigated. METHODS: Transcriptomic profiling was applied in FFPE tissues from 103 ESCC patients, including surgical samples from 66 treatment-naïve patients with long-term follow-up, and endoscopic biopsies from 37 local advanced ESCC cases receiving neoadjuvant immunotherapy plus chemotherapy. Unsupervised clustering indicated an aggressive phenotype with mesenchymal character in 66 treatment-naïve samples. Univariant logistic regression was applied to identify candidate biomarkers potentially predicted resistance to neoadjuvant immunotherapy within the range of mesenchymal phenotype enriched genes. These biomarkers were further validated by immunohistochemistry. Putative mechanisms mediating immunotherapy resistance, as indicated by microenvironment and immune cell infiltration, were evaluated by transcriptomic data, and validated by multiplex immunofluorescence. RESULTS: PLEK2 and IFI6, highly expressed in mesenchymal phenotype, were identified as novel biomarkers relating to non-MPR in neoadjuvant immunotherapy cohort [PLEK2high, OR (95% CI): 2.15 (1.07-4.33), P = 0.032; IFI6high, OR (95% CI): 2.21 (1.16-4.23), P = 0.016). PLEK2high and IFI6 high ESCC patients (versus low expressed patients) further exhibit higher chance of non-major pathological remissions (90%, P = 0.004) in neoadjuvant immunotherapy cohort and high mortality (78.9%, P = 0.05), poor prognosis in retrospective cohort. PLEK2high/IFI6high ESCC recapitulated mesenchymal phenotype, characterized by extracellular matrix composition and matrix remodeling. In addition, PLEK2high or IFI6high ESCC displayed an immune-unfavored microenvironment, represented by positive correlating with regulatory T cells, Helper 2 T cell as well as less infiltration of B cells, effector T cells and mast cells. CONCLUSIONS: PLEK2 and IFI6 was discovered of first time to identify a distinct ESCC subpopulation cannot be benefited from neoadjuvant immunotherapy and present a poor survival, which putatively associated with mesenchymal and immune-suppressive microenvironment.
BACKGROUND: Immunotherapy has largely improved clinical outcome of patients with esophageal squamous cell carcinoma (ESCC). However, a proportion of patients still fail to benefit. Thus, biomarkers predicting therapeutic resistance and underlying mechanism needs to be investigated. METHODS: Transcriptomic profiling was applied in FFPE tissues from 103 ESCC patients, including surgical samples from 66 treatment-naïve patients with long-term follow-up, and endoscopic biopsies from 37 local advanced ESCC cases receiving neoadjuvant immunotherapy plus chemotherapy. Unsupervised clustering indicated an aggressive phenotype with mesenchymal character in 66 treatment-naïve samples. Univariant logistic regression was applied to identify candidate biomarkers potentially predicted resistance to neoadjuvant immunotherapy within the range of mesenchymal phenotype enriched genes. These biomarkers were further validated by immunohistochemistry. Putative mechanisms mediating immunotherapy resistance, as indicated by microenvironment and immune cell infiltration, were evaluated by transcriptomic data, and validated by multiplex immunofluorescence. RESULTS: PLEK2 and IFI6, highly expressed in mesenchymal phenotype, were identified as novel biomarkers relating to non-MPR in neoadjuvant immunotherapy cohort [PLEK2high, OR (95% CI): 2.15 (1.07-4.33), P = 0.032; IFI6high, OR (95% CI): 2.21 (1.16-4.23), P = 0.016). PLEK2high and IFI6 high ESCC patients (versus low expressed patients) further exhibit higher chance of non-major pathological remissions (90%, P = 0.004) in neoadjuvant immunotherapy cohort and high mortality (78.9%, P = 0.05), poor prognosis in retrospective cohort. PLEK2high/IFI6high ESCC recapitulated mesenchymal phenotype, characterized by extracellular matrix composition and matrix remodeling. In addition, PLEK2high or IFI6high ESCC displayed an immune-unfavored microenvironment, represented by positive correlating with regulatory T cells, Helper 2 T cell as well as less infiltration of B cells, effector T cells and mast cells. CONCLUSIONS: PLEK2 and IFI6 was discovered of first time to identify a distinct ESCC subpopulation cannot be benefited from neoadjuvant immunotherapy and present a poor survival, which putatively associated with mesenchymal and immune-suppressive microenvironment.
Authors: Charlene M Fares; Eliezer M Van Allen; Charles G Drake; James P Allison; Siwen Hu-Lieskovan Journal: Am Soc Clin Oncol Educ Book Date: 2019-05-17
Authors: Jaffer A Ajani; Thomas A D'Amico; David J Bentrem; Joseph Chao; Carlos Corvera; Prajnan Das; Crystal S Denlinger; Peter C Enzinger; Paul Fanta; Farhood Farjah; Hans Gerdes; Michael Gibson; Robert E Glasgow; James A Hayman; Steven Hochwald; Wayne L Hofstetter; David H Ilson; Dawn Jaroszewski; Kimberly L Johung; Rajesh N Keswani; Lawrence R Kleinberg; Stephen Leong; Quan P Ly; Kristina A Matkowskyj; Michael McNamara; Mary F Mulcahy; Ravi K Paluri; Haeseong Park; Kyle A Perry; Jose Pimiento; George A Poultsides; Robert Roses; Vivian E Strong; Georgia Wiesner; Christopher G Willett; Cameron D Wright; Nicole R McMillian; Lenora A Pluchino Journal: J Natl Compr Canc Netw Date: 2019-07-01 Impact factor: 11.908