TCF1⁺PD-1⁺ tumour-infiltrating lymphocytes predict a favorable response and prolonged survival after immune checkpoint inhibitor therapy for non-small-cell lung cancer

Background: T-cell factor 1 (TCF1)⁺Programmed cell death-1 (PD-1)⁺ tumour-infiltrating lymphocytes (TILs) are a recently defined subset of exhausted T-cells (Texh-cells) that exhibit a progenitor phenotype. They have been associated with a response to immune checkpoint inhibitor (ICI) therapy in murine tumour models and in patients with malignant melanoma. We investigated the significance of TCF1⁺PD-1⁺ TILs as a predictive biomarker for ICI therapy response in non-small-cell lung cancer (NSCLC). Methods: Two different cohorts of NSCLC patients treated with ICI targeting the PD-1/PD-L1 pathway were included. RNA-seq was performed using NSCLC tissues obtained from 234 patients prior to immunotherapy (RNA-seq cohort). Double immunostaining of TCF1 and PD-1 and single immunostaining of other immunologic markers were performed in resected tumour tissues from another 116 patients (immunohistochemistry cohort). Results: In the RNA-seq cohort, both Texh-cell and progenitor Texh-cell gene sets were enriched in responders compared with non-responders. Larger Texh-cell fractions and increased progenitor Texh-cell gene sets were significantly associated with better progression-free survival (PFS). In the immunohistochemistry cohort, the TCF1⁺PD-1⁺ TIL number and PD-L1 tumour proportion score were significantly higher in responders than in non-responders. A high number of TCF1⁺PD-1⁺ TILs was significantly associated with both PFS and overall survival (OS) after ICI therapy, and it independently predicted a better PFS and OS according to multivariate analysis. Conclusion: TCF1⁺PD-1⁺ TILs, representing progenitor Texh-cells, predict both better response and survival in NSCLC patients after ICI therapy. Thus, they may be a useful predictive biomarker for ICI therapy in NSCLC.