Inhibition of MAN2A1 Enhances the Immune Response to Anti-PD-L1 in Human Tumors.
Inhibition of MAN2A1 Enhances the Immune Response to Anti-PD-L1 in Human Tumors.
复制标题
MAN 2A 1的抑制增强了人类肿瘤中对抗PD-L1的免疫应答。
DOI：
10.1158/1078-0432.ccr-20-0778
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发表时间：
2020-11-15
期刊：
影响因子：
--
通讯作者：
Liu XS
中科院分区：
文献类型：
--
作者：
Shi S;Gu S;Han T;Zhang W;Huang L;Li Z;Pan D;Fu J;Ge J;Brown M;Zhang P;Jiang P;Wucherpfennig KW;Liu XS
免疫检查点阻断已显示出显著的疗效，但仅在少数癌症患者中，这表明需要开发额外的治疗策略。由于聚糖生物合成中关键酶的表达失调而导致的肿瘤中的异常糖基化调节免疫应答。然而，聚糖生物合成酶在抗肿瘤免疫中的作用知之甚少。我们的目的是研究这些酶的免疫调节作用。我们整合了未经治疗的人类肿瘤的转录谱和功能性CRISPR筛选，以鉴定具有免疫调节作用的糖代谢酶基因。我们使用体外共培养和体内同基因肿瘤生长测定进一步验证了我们的发现。我们确定MAN 2A 1，编码N-聚糖成熟的酶，作为一个关键的免疫调节基因。对公共免疫检查点阻断试验数据的分析也表明了MAN 2A 1抑制和抗PD-L1治疗之间的协同作用。癌细胞中Man 2a 1的缺失增加了它们对T细胞介导的杀伤的敏感性。Man 2a 1敲除增强了对抗PD-L1治疗的应答，并促进了抗PD-L1治疗下肿瘤中更高的细胞毒性T细胞浸润。此外，MAN 2A 1的药理学抑制剂苦马豆素在同基因黑色素瘤和肺癌模型中与抗PD-L1协同作用，而单独的每种治疗几乎没有效果。Man 2a 1缺失使癌细胞更容易受到T细胞介导的杀伤。苦马豆素与抗PD-L1协同抑制肿瘤生长。鉴于抗PD-L1的有限疗效和苦马豆素的II期临床试验失败，我们的研究揭示了将两者结合以克服肿瘤免疫逃避的潜在疗法。
Immune checkpoint blockade has shown remarkable efficacy, but in only a minority of patients with cancer, suggesting the need to develop additional treatment strategies. Aberrant glycosylation in tumors, resulting from the dysregulated expression of key enzymes in glycan biosynthesis, modulates the immune response. However, the role of glycan biosynthesis enzymes in antitumor immunity is poorly understood. We aimed to study the immunomodulatory effects of these enzymes. We integrated transcriptional profiles of treatment-naïve human tumors and functional CRISPR screens to identify glycometabolism genes with immunomodulatory effects. We further validated our findings using in vitro coculture and in vivo syngeneic tumor growth assays. We identified MAN2A1, encoding an enzyme in N-glycan maturation, as a key immunomodulatory gene. Analyses of public immune checkpoint blockade trial data also suggested a synergy between MAN2A1 inhibition and anti–PD-L1 treatment. Loss of Man2a1 in cancer cells increased their sensitivity to T-cell–mediated killing. Man2a1 knockout enhanced response to anti–PD-L1 treatment and facilitated higher cytotoxic T-cell infiltration in tumors under anti–PD-L1 treatment. Furthermore, a pharmacologic inhibitor of MAN2A1, swainsonine, synergized with anti–PD-L1 in syngeneic melanoma and lung cancer models, whereas each treatment alone had little effect. Man2a1 loss renders cancer cells more susceptible to T-cell–mediated killing. Swainsonine synergizes with anti–PD-L1 in suppressing tumor growth. In light of the limited efficacy of anti–PD-L1 and failed phase II clinical trial on swainsonine, our study reveals a potential therapy combining the two to overcome tumor immune evasion.
影响因子：
7.8
作者：
Cornil, I;Kerbel, R S;Dennis, J W
通讯作者：
Dennis, J W