Sarafan ChEM-H, Stanford University, Stanford, CA 94305.
Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305.
Proc Natl Acad Sci U S A. 2023 Mar 14;120(11):e2215376120. doi: 10.1073/pnas.2215376120. Epub 2023 Mar 10.
The Siglecs (sialic acid-binding immunoglobulin-like lectins) are glycoimmune checkpoint receptors that suppress immune cell activation upon engagement of cognate sialoglycan ligands. The cellular drivers underlying Siglec ligand production on cancer cells are poorly understood. We find the oncogene causally regulates Siglec ligand production to enable tumor immune evasion. A combination of glycomics and RNA-sequencing of mouse tumors revealed the oncogene controls expression of the sialyltransferase and induces a glycan known as disialyl-T. Using in vivo models and primary human leukemias, we find that disialyl-T functions as a "don't eat me" signal by engaging macrophage Siglec-E in mice or the human ortholog Siglec-7, thereby preventing cancer cell clearance. Combined high expression of and identifies patients with high-risk cancers and reduced tumor myeloid infiltration. MYC therefore regulates glycosylation to enable tumor immune evasion. We conclude that disialyl-T is a glycoimmune checkpoint ligand. Thus, disialyl-T is a candidate for antibody-based checkpoint blockade, and the disialyl-T synthase ST6GALNAC4 is a potential enzyme target for small molecule-mediated immune therapy.
Siglecs（唾液酸结合免疫球蛋白样凝集素）是糖免疫检查点受体，在与同源唾液酸化糖链配体结合后抑制免疫细胞的激活。癌细胞上 Siglec 配体产生的细胞驱动因素尚不清楚。我们发现致癌基因 可因果调节 Siglec 配体的产生，从而实现肿瘤免疫逃逸。对小鼠肿瘤的糖组学和 RNA 测序的综合分析表明，致癌基因 控制着唾液酸转移酶 的表达，并诱导一种称为双唾液酸-T 的聚糖。通过体内模型和原发性人类白血病，我们发现双唾液酸-T 通过与小鼠中的巨噬细胞 Siglec-E 或人类同源物 Siglec-7 结合，充当“不要吃我”信号，从而防止癌细胞清除。 和 的高表达共同确定了具有高风险癌症和肿瘤髓样细胞浸润减少的患者。因此，MYC 调节糖基化以实现肿瘤免疫逃逸。我们得出结论，双唾液酸-T 是一种糖免疫检查点配体。因此，双唾液酸-T 是抗体为基础的检查点阻断的候选物，双唾液酸-T 合酶 ST6GALNAC4 是小分子介导免疫治疗的潜在酶靶标。
