Expression of the mono-ADP-ribosyltransferase ART1 by tumor cells mediates immune resistance in non-small cell lung cancer.
Expression of the mono-ADP-ribosyltransferase ART1 by tumor cells mediates immune resistance in non-small cell lung cancer.
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DOI：
10.1126/scitranslmed.abe8195
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发表时间：
2022-03-16
影响因子：
17.1
通讯作者：
中科院分区：
文献类型：
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作者：
大多数非小细胞肺癌（NSCLC）患者不能从免疫检查点抑制剂中获得持久的临床应答，这表明存在其他耐药机制。NAD诱导的表达P2 X7受体（P2 X7 R）的T细胞的细胞死亡（NICD）调节炎症组织中的免疫稳态。这一过程是由单ADP核糖基转移酶（ART）介导的。我们发现肿瘤细胞上ART 1的膜表达与CD 8 T细胞浸润减少之间存在关联。具体而言，我们观察到人肺腺癌中P2 X7 R + CD 8 T细胞亚群减少。在体外，P2 X7 R + CD 8 T细胞易受ART 1介导的ADP-核糖基化和NICD的影响，在阻断NAD+降解ADP-核糖基环化酶CD 38后加剧。最后，在小鼠非小细胞肺癌和黑色素瘤模型中，我们证明遗传和抗体介导的ART 1抑制以CD 8 T细胞依赖性方式减缓肿瘤生长。这与活化的P2 X7 R + CD 8 T细胞向肿瘤中的浸润增加有关。总之，我们将ART 1介导的NICD描述为NSCLC免疫耐药的机制，并提供了临床前证据，表明抗体介导的ART 1靶向治疗可以改善肿瘤控制，支持在临床研究中追求这种方法。肿瘤细胞表达的ART 1通过NAD诱导的细胞死亡消除CD 8 T细胞，驱动肺癌的免疫逃逸。
A majority of patients with non-small-cell lung cancer (NSCLC) do not achieve durable clinical responses from immune checkpoint inhibitors, suggesting the existence of additional resistance mechanisms. NAD-induced cell death (NICD) of P2X7-receptor (P2X7R)-expressing T cells regulates immune homeostasis in inflamed tissues. This process is mediated by mono-ADP-ribosyltransferases (ARTs). We found an association between membranous expression of ART1 on tumor cells and reduced CD8 T cell infiltration. Specifically, we observed a reduction in the P2X7R+ CD8 T cell subset in human lung adenocarcinomas. In vitro, P2X7R+ CD8 T cells were susceptible to ART1-mediated ADP-ribosylation and NICD, which was exacerbated upon blockade of the NAD+-degrading ADP-ribosyl cyclase CD38. Finally, in murine NSCLC and melanoma models, we demonstrate that genetic and antibody-mediated ART1 inhibition slowed tumor growth in a CD8 T cell-dependent manner. This was associated with increased infiltration of activated P2X7R+CD8 T cells into tumors. In conclusion, we describe ART1-mediated NICD as a mechanism of immune resistance in NSCLC and provide pre-clinical evidence that antibody-mediated targeting of ART1 can improve tumor control, supporting pursuit of this approach in clinical studies. Tumor cell-expressed ART1 eliminates CD8 T cells through NAD-induced cell death, driving immune escape in lung cancer.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
2.9
作者：
Boldrini L;Giordano M;Alì G;Melfi F;Romano G;Lucchi M;Fontanini G
通讯作者：
Fontanini G
影响因子：
16.6
作者：
Nizard M;Roussel H;Diniz MO;Karaki S;Tran T;Voron T;Dransart E;Sandoval F;Riquet M;Rance B;Marcheteau E;Fabre E;Mandavit M;Terme M;Blanc C;Escudie JB;Gibault L;Barthes FLP;Granier C;Ferreira LCS;Badoual C;Johannes L;Tartour E
通讯作者：
Tartour E
影响因子：
8
作者：
Markowitz, Geoffrey J.;Havel, Lauren S.;Mittal, Vivek
通讯作者：
Mittal, Vivek
影响因子：
32.4
作者：
Borges da Silva H;Peng C;Wang H;Wanhainen KM;Ma C;Lopez S;Khoruts A;Zhang N;Jameson SC
通讯作者：
Jameson SC