Background: With recent approval of mAb targeting PD-1 and PD-L1 for non–small cell lung cancer (NSCLC), extensive efforts are under way to develop predictive biomarkers for anti PD-1/PD-L1 response. PD-L1 expression upon histology is currently the only clinically available biomarker, but mRNA immune signatures are also emerging. While the efficacy of these drugs is dependent on CD8 T-cells, no study has evaluated both CD8 and PD-L1 as biomarkers. Methods: CD8 and PD-L1 expression was studied by RNA sequencing and immunohistochemistry (IHC). We used RNA sequencing data from The Cancer Genome Atlas (TCGA) lung cancer samples as a prognostic cohort. We validated the results obtained from the transcriptomic data with IHC data using another prognostic cohort of 34 metastatic NSCLC tumor samples untreated by immunotherapy and stained using CD8 and PD-L1. A predictive study was conducted on 85 NSCLC patients treated with nivolumab, for whom outcome was known. To evaluate our signature, we used IFN and Immune Expanded Signature (IES), previously described as gold standards. Data were externally validated using public data (GSE93157). Results: In the prognostic TCGA mRNA cohort, we observed that high CD8 expression is associated with better overall survival, while PD-L1 expression is associated with poor prognosis. CD8 and PD-L1 determined upon IHC also had prognostic value in the prognostic cohort. In the predictive cohort, CD8 and PD-L1 expression evaluated using mRNA or IHC are associated with better progression-free survival in patients treated with nivolumab. Use of mRNA improved discrimination when compared with histological measures. A combination of both CD8 and PDL1 variables was highly predictive of outcome and remained significant after adjustment for usual clinical variables (age, sex, histology performance status). This 2-gene signature using CD8 and PD-L1 outperformed both IFN and EIG signatures, even with IHC data. Similar results were obtained in the external validation cohort (GSE93157). Conclusions: CD8 and PD-L1 mRNA or IHC could be used to address NSCLC outcomes for patients treated with nivolumab.