Association of KDR mutation with better clinical outcomes in pan-cancer for immune checkpoint inhibitors

Yanan Cui; Pengpeng Zhang; Xiao Liang; Jiali Xu; Xinyin Liu; Yuemin Wu; Junling Zhang; Wei Wang; Fang Zhang; Renhua Guo

Association of KDR mutation with better clinical outcomes in pan-cancer for immune checkpoint inhibitors

Am J Cancer Res. 2022 Apr 15;12(4):1766-1783. eCollection 2022.

Authors

Yanan Cui¹, Pengpeng Zhang², Xiao Liang¹, Jiali Xu¹, Xinyin Liu¹, Yuemin Wu¹, Junling Zhang³, Wei Wang², Fang Zhang⁴, Renhua Guo¹

Affiliations

¹ Department of Oncology, The First Affiliated Hospital of Nanjing Medical University Nanjing, Jiangsu, China.
² Department of Thoracic Surgery, The First Affiliated Hospital of Nanjing Medical University Nanjing, Jiangsu, China.
³ The Medical Department, 3D Medicines Inc. Shanghai, China.
⁴ Department of Rheumatology and Immunology, Jiangsu Province Academy of Traditional Chinese Medicine Nanjing, Jiangsu, China.

PMID: 35530271
PMCID: PMC9077071

Abstract

Kinase insert domain receptor (KDR) activation is associated with the immunosuppressive microenvironment. However, the efficacy of immunotherapy in patients with KDR mutations is still unclear. To investigate the relationship between KDR gene mutations and the prognosis of pan-cancer, and whether immune checkpoint inhibitors (ICIs) may improve the prognosis of patients with KDR mutations, we analyzed public cohorts of pan-cancer immunotherapeutic patients including genomic and clinical data.Further analysis was performed on an internal validation data set including 67 non-small cell lung cancer. Through bioinformatics analysis, potential mechanism was studied in TCGA data. We found better responses to ICIs in patients with KDR mutation from pan-cancer public datasets (objective response rate [ORR], 45.0% vs 25.1%, P=0.0058; progression-free survival [PFS], P=0.039, HR=0.586, 95% CI 0.353-0.973) and validation cohort (overall survival (OS), P=0.05, HR=0.62; 95% CI, 0.38-1.00). Our NSCLC cohort verified the value of KDR mutation in predicting better clinical outcomes, including ORR (70.0% vs 22.81%, P=0.0057) and PFS (HR=0.158; 95% CI, 0.045-0.773, P=0.007). KDR mutation was associated with tumor mutation burden high, neoantigen burden and immune cellular activities. Meanwhile, KDR mutation was indicative of an immune-hot status, characterized by higher expression of PD-L1 and abundance of cytotoxic lymphocytes. KDR mutations may be potential positive predictors for pan-cancer received ICIs.

Keywords: KDR; NSCLC; biomarker; immune checkpoint inhibitors; pan-cancer.