IGFBP1<sup>hi</sup>WNT3A<sup>lo</sup> Subtype in Esophageal Cancer Predicts Response and Prolonged Survival with PD-(L)1 Inhibitor
Meichen Liu,
Wanpu Yan,
Dongbo Chen,
Jiancheng Luo,
Liang Dai,
Hongsong Chen,
Ke-Neng Chen
Affiliations
Meichen Liu
Department of Thoracic Surgery I, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, No. 52, Fucheng Road, Haidian District, Beijing 100142, China
Wanpu Yan
Department of Thoracic Surgery I, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, No. 52, Fucheng Road, Haidian District, Beijing 100142, China
Dongbo Chen
Peking University People’s Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Disease, No.11 Xizhimen South Street, Xicheng District, Beijing 100044, China
Jiancheng Luo
Aiyi Technology Co., Ltd., Room 1004, Building 3, Greenland Qihang, Biomedical Industry Base, Daxing District, Beijing 102629, China
Liang Dai
Department of Thoracic Surgery I, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, No. 52, Fucheng Road, Haidian District, Beijing 100142, China
Hongsong Chen
Peking University People’s Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Disease, No.11 Xizhimen South Street, Xicheng District, Beijing 100044, China
Ke-Neng Chen
Department of Thoracic Surgery I, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, No. 52, Fucheng Road, Haidian District, Beijing 100142, China
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.
