Tumor-immune microenvironment and NRF2 associate with clinical efficacy of PD-1 blockade combined with chemotherapy in lung squamous cell carcinoma

Cell Rep Med. 2023 Dec 19;4(12):101302. doi: 10.1016/j.xcrm.2023.101302. Epub 2023 Dec 4.


The RATIONALE-307 study (ClinicalTrials.gov: NCT03594747) demonstrates prolonged progression-free survival (PFS) with first-line tislelizumab plus chemotherapy versus chemotherapy in advanced lung squamous cell carcinoma (LUSC; N = 360). Here we describe an immune-related gene expression signature (GES), composed of genes involved in both innate and adaptive immunity, that appears to differentiate tislelizumab plus chemotherapy PFS benefit versus chemotherapy. In contrast, a tislelizumab plus chemotherapy PFS benefit is observed regardless of programmed death ligand 1 (PD-L1) expression or tumor mutational burden (TMB). Genetic analysis reveals that NRF2 pathway activation is enriched in PD-L1positive and TMBhigh patients. NRF2 pathway activation is negatively associated with PFS, which affects efficacy outcomes associated with PD-L1 and TMB status, impairing their predictive potential. Mechanistic studies demonstrate that NRF2 directly mediates PD-L1 constitutive expression independent of adaptive PD-L1 regulation in LUSC. In summary, the GES is an immune signature that might identify LUSC patients likely to benefit from first-line tislelizumab plus chemotherapy.

Keywords: NRF2; PD-1 blockade; PD-L1; biomarkers; clinical trial; gene expression signature; immunotheraphy; squamous NSCLC; tislelizumab; tumor mutational burden.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B7-H1 Antigen / genetics
  • Biomarkers, Tumor / genetics
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Carcinoma, Squamous Cell* / drug therapy
  • Carcinoma, Squamous Cell* / genetics
  • Carcinoma, Squamous Cell* / pathology
  • Humans
  • Lung / pathology
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / pathology
  • Mutation
  • NF-E2-Related Factor 2 / genetics
  • Programmed Cell Death 1 Receptor
  • Treatment Outcome
  • Tumor Microenvironment / genetics


  • B7-H1 Antigen
  • Biomarkers, Tumor
  • NF-E2-Related Factor 2
  • Programmed Cell Death 1 Receptor
  • NFE2L2 protein, human

Associated data

  • ClinicalTrials.gov/NCT03594747