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

• Published in: Cell reports. Medicine 2023-12, Vol.4 (12), p.101302-101302, Article 101302
• Main Authors: Duan, Jianchun, Zhang, Yun, Chen, Ran, Liang, Liang, Huo, Yi, Lu, Shun, Zhao, Jun, Hu, Chunhong, Sun, Yuping, Yang, Kunyu, Chen, Mingwei, Yu, Yan, Ying, Jianming, Huang, Ruiqi, Ma, Xiaopeng, Leaw, Shiangjiin, Bai, Fan, Shen, Zhirong, Cai, Shangli, Gao, Daming, Wang, Jie, Wang, Zhijie
• Format: Article
• Language: English
• Subjects: 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
• ISSN: 2666-3791; 2666-3791
• DOI: 10.1016/j.xcrm.2023.101302

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-L1 and TMB 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.