Limited benefit population of immune checkpoint inhibitors makes it urgent to screen predictive biomarkers for stratifying the patients.Herein,we have investigated peripheral CD4+T cell signatures in advanced non-small cell lung cancer(NSCLC)patients receiving anti-PD-1/PD-L1 treatments.It was found that the percentages of IFN-γ and IL-17A secreting na?ve CD4+T cells(Tn),and memory CD4+T cells(Tm)expressing PD-1,PD-L1 and CTLA-4 were significantly higher in responder(R)than non-responder(NonR)NSCLC patients associated with a longer progression free survival(PFS).Logistic regression analysis revealed that the baseline IFN-γ-producing CD4+Tn cells and PD-1+CD4+Tm cells were the most significant signatures with the area under curve(AUC)value reaching 0.849.This was further validated in another anti-PD-1 monotherapy cohort.Conversely,high percentage of CTLA-4+CD4+Tm cells was associated with a shorter PFS in patients receiving anti-PD-L1 monotherapy.Our study therefore elucidates the significance of functional CD4+Tn and Tm subpopulations before the treatment in predicting the responses to anti-PD-1 treatment in Chinese NSCLC patients.The fact that there display distinct CD4+T cell signatures in the prediction to anti-PD-1 and anti-PD-L1 monotherapy from our study provides preliminary evidence on the feasibility of anti-PD-1 and anti-PD-L1 combination therapy for advanced NSCLC patients.