The superior efficacy of anti-PD-1/PD-L1 immunotherapy in KRAS-mutant non-small cell lung cancer that correlates with an inflammatory phenotype for updates and increased immunogenicity

被引:208
作者
Liu, Chengming [1 ]
Zheng, Sufei [1 ]
Jin, Runsen [1 ]
Wang, Xinfeng [1 ]
Wang, Feng [1 ]
Zang, Ruochuan [1 ]
Xu, Haiyan [2 ]
Lu, Zhiliang [1 ]
Huang, Jianbing [1 ]
Lei, Yuanyuan [1 ]
Mao, Shuangshuang [1 ]
Wang, Yalong [1 ]
Feng, Xiaoli [3 ]
Sun, Nan [1 ]
Wang, Yan [2 ]
He, Jie [1 ]
机构
[1] Chinese Acad Med Sci & Peking Union Med Coll, Canc Hosp, Natl Clin Res Ctr Canc, Dept Thorac Surg,Natl Canc Ctr, Beijing 100021, Peoples R China
[2] Chinese Acad Med Sci & Peking Union Med Coll, Canc Hosp, Natl Clin Res Ctr Canc, Dept Med Oncol,Natl Canc Ctr, Beijing 100021, Peoples R China
[3] Chinese Acad Med Sci & Peking Union Med Coll, Canc Hosp, Natl Clin Res Ctr Canc, Dept Pathol,Natl Canc Ctr, Beijing 100021, Peoples R China
基金
中国国家自然科学基金;
关键词
KRAS; PD-L1; TILs; TMB; NSCLC; CHECKPOINT INHIBITORS; PREDICTIVE-VALUE; IMMUNE ESCAPE; PD-1; BLOCKADE; OPEN-LABEL; SENSITIVITY; DOCETAXEL; MUTATION; TUMORS; RAS;
D O I
10.1016/j.canlet.2019.10.027
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Immune checkpoint inhibitors against PD-1/PD-L1 yield improved survival rates of KRAS-mutant NSCLC patients, who conferred a poor prognosis without effective targeted therapy until now. Yet, the underlying association between KRAS mutations and immune responses remains unclear. We performed an integrated analysis of the data from publicly available repositories and from clinical center cohorts to explore the association between KRAS mutation status and tumor immunity-associated features, including PD-Li expression, CDS+ tumor-infiltrating lymphocytes (TILs) and tumor mutational burden (TMB). Our results revealed that KRAS mutations are correlated with an inflammatory tumor microenvironment and tumor immunogenicity, resulting in superior patient response to PD-1/PD-L1 inhibitors. Meanwhile, three-pool analysis further confirmed that KRAS-mutant NSCLC patients show remarkable clinical benefit from anti-PD-1/PD-L1 immunotherapy. In addition, a KRAS-mutant lung adenocarcinoma mouse model was established to estimate the relative efficacy of anti-PD-L1 monoclonal antibody monotherapy or combination treatment with docetaxel versus docetaxel alone. Most surprisingly, we found that PD-L1 blockade combined with docetaxel did not promote an anti-tumor response. These findings uncover that PD-1/PD-L1 blockade monotherapy may be the optimal therapeutic schedule in NSCLC patients harboring KRAS mutations.
引用
收藏
页码:95 / 105
页数:11
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