Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan; Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Biochem Biophys Res Commun. 2022 Jun 18;609:183-188. doi: 10.1016/j.bbrc.2022.04.035. Epub 2022 Apr 10.
Effective cancer immunotherapy requires physical contact of T cells with cancer cells. However, tumors often constitute special microenvironments that exclude T cells and resist immunotherapy. Cholesterol sulfate (CS) is a product of sulfotransferase SULT2B1b and acts as an endogenous inhibitor of DOCK2, a Rac activator essential for migration and activation of lymphocytes. We have recently shown that cancer-derived CS prevents tumor infiltration by effector T cells. Therefore, SULT2B1b may be a therapeutic target to dampen CS-mediated immune evasion. Here, we identified 3β-hydroxy-5-cholenoic acid (3β-OH-5-Chln) as a cell-active inhibitor of SULT2B1b. 3β-OH-5-Chln inhibited the cholesterol sulfotransferase activity of SULT2B1b in vitro and suppressed CS production from cancer cells expressing SULT2B1b. In vivo administration of 3β-OH-5-Chln locally reduced CS level in murine CS-producing tumors and increased infiltration of CD8 T cells. When combined with immune checkpoint blockade or antigen-specific T cell transfer, 3β-OH-5-Chln suppressed the growth of CS-producing tumors. These results demonstrate that pharmacological inhibition of SULT2B1b can promote antitumor immunity through suppressing CS-mediated T cell exclusion.
有效的癌症免疫疗法需要 T 细胞与癌细胞进行物理接触。然而，肿瘤通常构成特殊的微环境，排斥 T 细胞并抵抗免疫疗法。硫酸胆固醇（CS）是 SULT2B1b 转移酶的产物，作为 DOCK2 的内源性抑制剂，DOCK2 是淋巴细胞迁移和激活所必需的 Rac 激活剂。我们最近表明，癌症衍生的 CS 可防止效应 T 细胞浸润肿瘤。因此，SULT2B1b 可能是一种治疗靶点，可减弱 CS 介导的免疫逃逸。在这里，我们鉴定出 3β-羟基-5-胆甾烯酸（3β-OH-5-Chln）是 SULT2B1b 的细胞活性抑制剂。3β-OH-5-Chln 在体外抑制 SULT2B1b 的胆固醇磺基转移酶活性，并抑制表达 SULT2B1b 的癌细胞中 CS 的产生。3β-OH-5-Chln 的体内给药可局部降低小鼠产生 CS 的肿瘤中的 CS 水平并增加 CD8 T 细胞的浸润。当与免疫检查点阻断或抗原特异性 T 细胞转移联合使用时，3β-OH-5-Chln 可抑制产生 CS 的肿瘤的生长。这些结果表明，SULT2B1b 的药理抑制可通过抑制 CS 介导的 T 细胞排斥来促进抗肿瘤免疫。
