MYC-driven synthesis of Siglec ligands is a glycoimmune checkpoint.
MYC-driven synthesis of Siglec ligands is a glycoimmune checkpoint.
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DOI：
10.1073/pnas.2215376120
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发表时间：
2023-03-14
影响因子：
11.1
通讯作者：
Bertozzi, Carolyn R.
中科院分区：
文献类型：
--
作者：
Smith, Benjamin A. H.;Deutzmann, Anja;Correa, Kristina M.;Delaveris, Corleone S.;Dhanasekaran, Renumathy;Dove, Christopher G.;Sullivan, Delaney K.;Wisnovsky, Simon;Stark, Jessica C.;V. Pluvinage, John;Swaminathan, Srividya;Riley, Nicholas M.;Rajan, Anand;Majeti, Ravindra;Felsher, Dean W.;Bertozzi, Carolyn R.
MYC是人类癌症中最常见的失调癌基因之一。我们发现MYC可以调节癌细胞表面的糖基化，从而促进免疫逃避。使用MYC诱导的肿瘤发生的条件性转基因模型，我们发现MYC驱动肿瘤细胞上被称为二唾液酸-T的特定聚糖的展示。值得注意的是，二唾液酸-T聚糖与骨髓细胞上的特异性Siglec受体结合以抑制抗癌免疫应答，从而促进体内肿瘤生长。这些数据确定了MYC驱动的癌症上的恶性糖基化的特征，这表明了免疫治疗的潜在靶点。Siglecs（唾液酸结合免疫球蛋白样凝集素）是糖免疫检查点受体，其在接合同源唾液酸聚糖配体时抑制免疫细胞活化。对癌细胞上Siglec配体产生的细胞驱动因素知之甚少。我们发现MYC癌基因因果调节Siglec配体的产生，使肿瘤免疫逃避。小鼠肿瘤的糖组学和RNA测序的组合揭示了MYC癌基因控制唾液酸转移酶St 6 galnac 4的表达，并诱导称为二唾液酸-T的聚糖。使用体内模型和原发性人类白血病，我们发现disialyl-T通过在小鼠或人类直系同源物Siglec-7中接合巨噬细胞Siglec-E，从而阻止癌细胞清除，起到“不要吃我”信号的作用。MYC和ST 6 GALNAC 4的组合高表达鉴定具有高风险癌症和减少的肿瘤骨髓浸润的患者。因此，MYC调节糖基化以使肿瘤免疫逃避成为可能。我们得出结论，disialyl-T是糖免疫检查点配体。因此，二唾液酸-T是基于抗体的检查点阻断的候选者，并且二唾液酸-T合酶ST 6 GALNAC 4是小分子介导的免疫疗法的潜在酶靶标。
MYC is one of the most frequently dysregulated oncogenes in human cancer. We discover that MYC causally regulates glycosylation on the surface of cancer cells, which in turn facilitates immune evasion. Using a conditional transgenic model of MYC-induced tumorigenesis, we find that MYC drives the display of a particular glycan known as disialyl-T on tumor cells. Remarkably, the disialyl-T glycan engages specific Siglec receptors on myeloid cells to inhibit the anticancer immune response, thereby promoting tumor growth in vivo. These data identify a signature of malignant glycosylation on MYC-driven cancers that suggests potential targets for immunotherapy. 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 MYC oncogene causally regulates Siglec ligand production to enable tumor immune evasion. A combination of glycomics and RNA-sequencing of mouse tumors revealed the MYC oncogene controls expression of the sialyltransferase St6galnac4 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 MYC and ST6GALNAC4 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.
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DOI：
10.1126/science.aac9935
发表时间：
2016-04-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Casey SC;Tong L;Li Y;Do R;Walz S;Fitzgerald KN;Gouw AM;Baylot V;Gütgemann I;Eilers M;Felsher DW
通讯作者：
Felsher DW
DOI：
10.1038/s41580-020-0215-2
发表时间：
2020-05
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Baluapuri A;Wolf E;Eilers M
通讯作者：
Eilers M
影响因子：
8.6
作者：
Boike L;Cioffi AG;Majewski FC;Co J;Henning NJ;Jones MD;Liu G;McKenna JM;Tallarico JA;Schirle M;Nomura DK
通讯作者：
Nomura DK
影响因子：
7.7
作者：
Cappellen, David;Schlange, Thomas;Hynes, Nancy E.
通讯作者：
Hynes, Nancy E.
影响因子：
64.5
作者：
AYER, DE;KRETZNER, L;EISENMAN, RN
通讯作者：
EISENMAN, RN