title: Potential Predictive Value ofTP53andKRASMutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma.
abstract: Purpose:Although clinical studies have shown promise for targeting programmed cell death protein-1 (PD-1) and ligand (PD-L1) signaling in non-small cell lung cancer (NSCLC), the factors that predict which subtype patients will be responsive to checkpoint blockade are not fully understood.Experimental Design:We performed an integrated analysis on the multiple-dimensional data types including genomic, transcriptomic, proteomic, and clinical data from cohorts of lung adenocarcinoma public (discovery set) and internal (validation set) database and immunotherapeutic patients. Gene set enrichment analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups.Results:We observed thatTP53mutation significantly increased expression of immune checkpoints and activated T-effector and interferon-γ signature. More importantly, theTP53/KRAScomutated subgroup manifested exclusive increased expression of PD-L1 and a highest proportion ofPD-L1+/CD8A+Meanwhile,TP53-orKRAS-mutated tumors showed prominently increased mutation burden and specifically enriched in the transversion-high (TH) cohort. Further analysis focused on the potential molecular mechanism revealed thatTP53orKRASmutation altered a group of genes involved in cell-cycle regulating, DNA replication and damage repair. Finally, immunotherapeutic analysis from public clinical trial and prospective observation in our center were further confirmed thatTP53orKRASmutation patients, especially those with co-occurringTP53/KRASmutations, showed remarkable clinical benefit to PD-1 inhibitors.Conclusions:This work provides evidence thatTP53andKRASmutation in lung adenocarcinoma may be served as a pair of potential predictive factors in guiding anti-PD-1/PD-L1 immunotherapy.Clin Cancer Res; 23(12); 3012-24. ©2016 AACR.
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China.|Southern Medical University, Guangzhou, China.
authors.forename: Zhong-Yi
authors.initials: ZY
authors.lastname: Dong
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Wen-Zhao
authors.initials: WZ
authors.lastname: Zhong
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Xu-Chao
authors.initials: XC
authors.lastname: Zhang
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Su
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Xie
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Si-Yang
authors.initials: SY
authors.lastname: Liu
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Tu
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Hua-Jun
authors.initials: HJ
authors.lastname: Chen
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Yue-Li
authors.initials: YL
authors.lastname: Sun
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Jin-Ji
authors.initials: JJ
authors.lastname: Yang
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Xue-Ning
authors.initials: XN
authors.lastname: Yang
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Jia-Xin
authors.initials: JX
authors.lastname: Lin
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Hong-Hong
authors.initials: HH
authors.lastname: Yan
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China.|Southern Medical University, Guangzhou, China.
authors.forename: Hao-Ran
authors.initials: HR
authors.lastname: Zhai
authors.affiliation: Department of Pathology and Laboratory Medicine, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Li-Xu
authors.initials: LX
authors.lastname: Yan
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Ri-Qiang
authors.initials: RQ
authors.lastname: Liao
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Si-Pei
authors.initials: SP
authors.lastname: Wu
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. syylwu@live.cn.|Southern Medical University, Guangzhou, China.
authors.forename: Yi-Long
authors.initials: YL
authors.lastname: Wu
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics; D005260:Female; D006801:Humans; D007167:Immunotherapy; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008297:Male; D009154:Mutation; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000235:genetics*; D040901:Proteomics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; C117307:KRAS protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D016283:Proto-Oncogene Proteins p21(ras)