Unveiling the role of FTO polymorphisms in predicting response to immune checkpoint inhibitors: A retrospective study

Wenhui Liu; Chenlin Xiao; Jianquan Luo; Mouze Liu; Bao Sun; Zhiying Luo

doi:10.1016/j.intimp.2024.112142

Unveiling the role of FTO polymorphisms in predicting response to immune checkpoint inhibitors: A retrospective study

Int Immunopharmacol. 2024 Apr 25:133:112142. doi: 10.1016/j.intimp.2024.112142. Online ahead of print.

Authors

Wenhui Liu¹, Chenlin Xiao¹, Jianquan Luo¹, Mouze Liu¹, Bao Sun¹, Zhiying Luo²

Affiliations

¹ Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, PR China; Institute of Clinical Pharmacy, Central South University, Changsha, PR China.
² Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, PR China; Institute of Clinical Pharmacy, Central South University, Changsha, PR China. Electronic address: lzhy199089@csu.edu.cn.

PMID: 38669948
DOI: 10.1016/j.intimp.2024.112142

Abstract

Background: Identifying patients who can benefit from immune checkpoint inhibitors (ICIs) is a critical challenge in immunotherapy. This study aimed to investigate the association between fat mass and obesity-associated protein (FTO) polymorphisms and ICIs treatment outcomes.

Method: This retrospective study was conducted on 371 patients with malignant tumors who received ICIs treatment and were followed-up for a minimum duration of 12 months. Seven variants in FTO gene were genotyped using the Sequenome MassARRAY platform, and their associations with ICIs treatment outcomes were analyzed.

Results: Pharmacogenomic research revealed that individuals carrying the rs11075995AT/TT genotype were more likely to benefit from ICIs treatment compare to TT genotype. Cox regression analysis showed that rs1125338TT carriers exhibited a shorter progression-free survival (PFS, hazard ratio (HR) = 1.72, 95 % confidence interval (CI) = 1.12-2.46), while rs12596638GG carriers experienced extended PFS (HR = 0.71, 95 % CI = 0.50-0.99). Multiple Cox regression analysis indicated that rs12596638GG (HR = 6.81, 95 %CI = 1.20-38.56) and rs1125338CC (HR = 1.78, 95 %CI = 0.07-0.45), rs12600192CC (HR = 0.13, 95 %CI = 0.037-0.44) genotypes were independently associated with overall survival (OS) after adjusting clinical characteristics. Furthermore, patients with rs12600192CC genotype had a lower risk of severe irAEs compared to those with GG/GC genotypes (P < 0.01).

Conclusion: We identified FTO gene polymorphisms associated with treatment outcomes of ICI treatment in patients with multiple solid cancers, which might serve as potential predictive biomarkers.

Keywords: Anti-PD-1 blockade; Immune checkpoint inhibitors; Immune-related adverse events; Immunotherapy; Therapeutic biomarker.