IGFBP1hiWNT3Alo Subtype in Esophageal Cancer Predicts Response and Prolonged Survival with PD-(L)1 Inhibitor

PD-(L)1 inhibitor could improve the survival of locally advanced esophageal cancer (ESCA) patients, but we cannot tailor the treatment to common biomarkers. WNT signaling activation was associated with primary resistance to immunotherapy. In this study, we used our two clinical cohorts (BJCH n = 95, BJIM n = 21) and three public cohorts to evaluate and verify a new immunotherapeutic biomarker based on WNT signaling in ESCA patients. Our findings showed that WNT signaling-related genes stratified TCGA patients into Cluster 1, 2, and 3, among which, Cluster 3 had the worst prognosis. The most up- and down-regulated genes in Cluster 3 were IGFBP1 and WNT3A. Further analysis validated that IGFBP1hiWNT3Alo ESCA patients had significantly poor RFS and OS in the TCGA and BJCH cohorts. Interestingly, IGFBP1hiWNT3Alo patients had a good response and prognosis with immunotherapy in three independent cohorts, exhibiting better predictive value than PD-L1 expression (signature AUC = 0.750; PD-L1 AUC = 0.571). Moreover, IGFBP1hiWNT3Alo patients may benefit more from immunotherapy than standard treatment (p = 0.026). Immune cell infiltration analysis revealed a significant increase in DC infiltration in IGFBP1hiWNT3Alo patients post-immunotherapy (p = 0.022), which may enhance immune response. The IGFBP1hiWNT3Alo signature could predict patients who benefited from PD-(L)1 inhibitor treatment and may serve as a biomarker in ESCA.