Genetic insights into carbohydrate sulfotransferase 8 and its impact on the immunotherapy efficacy of cancer
Journal
Cell reports
Journal Volume
43
Journal Issue
1
Date Issued
2024-01-23
Author(s)
Chou, Wen-Cheng
Chen, Wei-Ting
Kuo, Chun-Tse
Chang, Yao-Ming
Li, Chia-Wei
Hung, Mien-Chie
Shen, Chen-Yang
Abstract
Immune checkpoint blockade (ICB) is a promising therapy for solid tumors, but its effectiveness depends on biomarkers that are not precise. Here, we utilized genome-wide association study to investigate the association between genetic variants and tumor mutation burden to interpret ICB response. We identified 16 variants (p < 5 × 10-8) probed to 17 genes on 9 chromosomes. Subsequent analysis of one of the most significant loci in 19q13.11 suggested that the rs111308825 locus at the enhancer is causal, as its A allele impairs KLF2 binding, leading to lower carbohydrate sulfotransferase 8 (CHST8) expression. Breast cancer cells expressing CHST8 suppress T cell activation, and Chst8 loss attenuates tumor growth in a syngeneic mouse model. Further investigation revealed that programmed death-ligand 1 (PD-L1) and its homologs could be sulfated by CHST8, resulting in M2-like macrophage enrichment in the tumor microenvironment. Finally, we confirmed that low-CHST8 tumors have better ICB response, supporting the genetic effect and clinical value of rs111308825 for ICB efficacy prediction.
Subjects
CP: Cancer; CP: Immunology; GWAS; GalNAc-4-ST1; KLF2; PD-L1; glycan sulfation; immune checkpoint blockade; macrophages; mannose receptor; single-nucleotide polymorphism; tumor mutation burden
Type
journal article