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    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. Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

    Citation

    Wen-Cheng Chou, Wei-Ting Chen, Chun-Tse Kuo, Yao-Ming Chang, Yen-Shen Lu, Chia-Wei Li, Mien-Chie Hung, Chen-Yang Shen. Genetic insights into carbohydrate sulfotransferase 8 and its impact on the immunotherapy efficacy of cancer. Cell reports. 2024 Jan 23;43(1):113641

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    PMID: 38165805

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