Systemic longitudinal immune profiling identifies proliferating Treg cells as predictors of immunotherapy benefit:biomarker analysis from the phase 3 CONTINUUM and DIPPER trials  

作　　者：Sai-Wei Huang Wei Jiang Sha Xu Yuan Zhang Juan Du Ya-Qin Wang Kun-Yu Yang Ning Zhang Fang Liu Guo-Rong Zou Feng Jin Hai-Jun Wu Yang-Ying Zhou Xiao-Dong Zhu Nian-Yong Chen Cheng Xu Han Qiao Na Liu Ying Sun Jun Ma Ye-Lin Liang Xu Liu 

机构地区：[1]Department of Radiation Oncology,State Key Laboratory of Oncology in South China,Collaborative Innovation Center of Cancer Medicine,Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy,Guangdong Provincial Clinical Research Center for Cancer,Sun Yat-sen University Cancer Center,Guangzhou,PR China [2]Department of Experimental Research,State Key Laboratory of Oncology in South China,Collaborative Innovation Center of Cancer Medicine,Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy,Guangdong Provincial Clinical Research Center for Cancer,Sun Yat-sen University Cancer Center,Guangzhou,PR China [3]Cancer Center,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,PR China [4]Department of Radiation Oncology,The First People’s Hospital of Foshan,Foshan,PR China [5]Department of Pathology,The First People’s Hospital of Foshan,Foshan,PR China [6]Department of Oncology,Panyu Central Hospital,Guangzhou,PR China [7]Department of Oncology,The Affiliated Cancer Hospital of Guizhou Medical University,Guiyang,PR China [8]Department of Oncology,Xiangya Hospital,Central South University,Changsha,PR China [9]Department of Radiation Oncology,Affiliated Tumor Hospital of Guangxi Medical University,Nanning,PR China [10]Department of Radiation Oncology,Cancer Center,West China Hospital,Sichuan University,Chengdu,PR China

出　　处：《Signal Transduction and Targeted Therapy》2024年第11期5297-5309,共13页信号转导与靶向治疗（英文）

基　　金：supported by grants from the National Natural Science Foundation of China(81930072,82101750,82172870,82202943,82373312,and 82403896);Natural Science Foundation of Guangdong Province(2024B1515020114);Science and Technology Plan Project of Guangzhou(2024A04J3943);Cancer Innovative Research Program of Sun Yat-sen University Cancer Center(CIRP-SYSUCC-0005);Chih Kuang Scholarship for Outstanding Young Physician-Scientists of Sun Yat-sen University Cancer Center(CKS-SYSUCC-2023004).

摘　　要：The identification of predictors for immunotherapy is often hampered by the absence of control groups in many studies,making it difficult to distinguish between prognostic and predictive biomarkers.This study presents biomarker analyses from the phase 3 CONTINUUM trial(NCT03700476),the first to show that adding anti-PD-1(aPD1)to chemoradiotherapy(CRT)improves event-free survival(EFS)in patients with locoregionally advanced nasopharyngeal carcinoma.A dynamic single-cell atlas was profiled using mass cytometry on peripheral blood mononuclear cell samples from 12 pairs of matched relapsing and non-relapsing patients in the aPD1-CRT arm.Using a supervised representation learning algorithm,we identified a Ki67+proliferating regulatory T cells(Tregs)population expressing high levels of activated and immunosuppressive molecules including FOXP3,CD38,HLA-DR,CD39,and PD-1,whose abundance correlated with treatment outcome.The frequency of these Ki67+Tregs was significantly higher at baseline and increased during treatment in patients who relapsed compared to non-relapsers.Further validation through flow cytometry(n=120)confirmed the predictive value of this Treg subset.Multiplex immunohistochemistry(n=249)demonstrated that Ki67+Tregs in tumors could predict immunotherapy benefit,with aPD1 improving EFS only in patients with low baseline levels of Ki67+Tregs.These findings were further validated in the multicenter phase 3 DIPPER trial(n=262,NCT03427827)and the phase 3 OAK trial of anti-PD-L1 immunotherapy in NSCLC,underscoring the predictive value of Ki67+Treg frequency in identifying the beneficiaries of immunotherapy and potentially guiding personalized treatment strategies.

关 键 词：PD1 IMMUNOTHERAPY PROLIFERATING 

分 类 号：R392[医药卫生—免疫学]