NKG2A and PD-L1 expression panel predicts clinical benefits from adjuvant chemotherapy and PD-L1 blockade in muscle-invasive bladder cancer

BACKGROUND: Programmed cell death ligand-1 (PD-L1) expression as a single biomarker for immune checkpoint blockade (ICB) was controversial. NKG2A was a PD1/PD-L1 axis-related immunity-dependent factor. NKG2A and PD-L1 expression as a combinatorial biomarker might improve the prediction of PD-L1 in patients with muscle-invasive bladder cancer (MIBC). METHODS: Three independent cohorts were enrolled in our study. 195 patients with bladder-derived metastatic urothelial carcinoma on PD-L1 inhibitor treatment from the IMvigor210 trial were enrolled. 124 MIBC patients from Zhongshan Hospital and 391 patients with MIBC from The Cancer Genome Atlas database were included in this study. The PD-L1/NKG2A-based risk stratification was validated in three independent cohorts, and its association with response to ICB and adjuvant chemotherapy (ACT), immune contexture and molecular features was evaluated. Histologic staining and genomic algorithm were performed to detect characteristics of NKG2A and PD-L1 expression and infiltration of immune cells. RESULTS: We identified NKG2A(hi)PD-L1(hi) patients could benefit more from cisplatin-based ACT and PD-L1 inhibitor. Further analyses revealed NKG2A and PD-L1 expression panel was linked to an immune-active tumor microenvironment with highly immune effector cells and effector molecules. In addition, NKG2A and PD-L1 expression panel was intrinsically correlated with genomic alterations related to therapeutic response in MIBC. CONCLUSIONS: NKG2A and PD-L1 expression panel was associated with an immune inflamed microenvironment and acted as a combinatorial biomarker to predict the therapeutic response to ACT and PD-L1 blockade in MIBC.