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

Eur J Cancer. 2022 Oct;174:10-20. doi: 10.1016/j.ejca.2022.07.004. Epub 2022 Aug 12.


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.

Keywords: Exhausted T cells; Immune checkpoint inhibitor; Immunotherapy; Non-small cell lung cancer; PD-1; Precursor exhausted T cells; Predictive biomarker; TCF1; Tumor microenvironment.

MeSH terms

  • Animals
  • B7-H1 Antigen / metabolism
  • CD8-Positive T-Lymphocytes
  • Carcinoma, Non-Small-Cell Lung* / pathology
  • Hepatocyte Nuclear Factor 1-alpha / metabolism
  • Humans
  • Immune Checkpoint Inhibitors / therapeutic use
  • Lung Neoplasms* / pathology
  • Lymphocytes, Tumor-Infiltrating
  • Mice
  • Programmed Cell Death 1 Receptor / metabolism


  • B7-H1 Antigen
  • Hepatocyte Nuclear Factor 1-alpha
  • Hnf1a protein, mouse
  • Immune Checkpoint Inhibitors
  • Programmed Cell Death 1 Receptor