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...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.展开更多
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)+2 种基金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).
文摘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.
