γδ T cells are effectors of immunotherapy in cancers with HLA class I defects.
γδ T cells are effectors of immunotherapy in cancers with HLA class I defects.
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DOI：
10.1038/s41586-022-05593-1
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发表时间：
2023-01
期刊：
影响因子：
64.8
通讯作者：
Voest, Emile E.
中科院分区：
文献类型：
--
作者：
de Vries, Natasja L.;van de Haar, Joris;Veninga, Vivien;Chalabi, Myriam;Ijsselsteijn, Marieke E.;van der Ploeg, Manon;van den Bulk, Jitske;Ruano, Dina;van den Berg, Jose G.;Haanen, John B.;Zeverijn, Laurien J.;Geurts, Birgit S.;de Wit, Gijs F.;Battaglia, Thomas W.;Gelderblom, Hans;Verheul, Henk M. W.;Schumacher, Ton N.;Wessels, Lodewyk F. A.;Koning, Frits;de Miranda, Noel F. C. C.;Voest, Emile E.
DNA 错配修复缺陷 (MMR-d) 癌症呈现出丰富的新抗原，这被认为解释了它们对免疫检查点阻断 (ICB) 的特殊反应。在这里，与其他癌症类型相比，我们观察到 21 种 (95%) β2-微球蛋白（由 B2M 编码）基因组失活的 MMR-d 癌症中有 20 种保留了对 ICB 的反应性，这表明在这种情况下除了 CD8+ T 细胞之外还有免疫效应细胞参与其中。接下来，我们发现 B2M 失活与 MMR-d 癌症中 γδ T 细胞浸润增加之间存在密切关联。这些 γδ T 细胞主要包含 Vδ1 和 Vδ3 亚群，并表达高水平的 PD-1、其他激活标记物，包括细胞毒性分子和多种杀伤细胞免疫球蛋白样受体。在体外，与抗原呈递能力良好的细胞相比，从 MMR-d 结肠癌中分离的 PD-1+ γδ T 细胞对人类白细胞抗原 (HLA)-I 类阴性 MMR-d 结肠癌细胞系和 B2M 敲除患者来源的肿瘤类器官表现出增强的反应性。通过比较 PD-1 和 CTLA-4 双重阻断前后获得的 MMR-d 结肠癌患者的配对肿瘤样本，我们发现免疫检查点阻断显着增加了 B2M 缺陷癌症中 γδ T 细胞的频率。总而言之，这些数据表明 γδ T 细胞有助于 HLA-I 类阴性 MMR-d 结肠癌患者对免疫检查点阻断的反应，并强调了 γδ T 细胞在癌症免疫治疗中的潜力。 γδ T 细胞有助于 HLA-I 类阴性 DNA 错配修复缺陷结肠癌患者对免疫检查点阻断治疗的反应。 。
DNA mismatch repair-deficient (MMR-d) cancers present an abundance of neoantigens that is thought to explain their exceptional responsiveness to immune checkpoint blockade (ICB). Here, in contrast to other cancer types, we observed that 20 out of 21 (95%) MMR-d cancers with genomic inactivation of β2-microglobulin (encoded by B2M) retained responsiveness to ICB, suggesting the involvement of immune effector cells other than CD8+ T cells in this context. We next identified a strong association between B2M inactivation and increased infiltration by γδ T cells in MMR-d cancers. These γδ T cells mainly comprised the Vδ1 and Vδ3 subsets, and expressed high levels of PD-1, other activation markers, including cytotoxic molecules, and a broad repertoire of killer-cell immunoglobulin-like receptors. In vitro, PD-1+ γδ T cells that were isolated from MMR-d colon cancers exhibited enhanced reactivity to human leukocyte antigen (HLA)-class-I-negative MMR-d colon cancer cell lines and B2M-knockout patient-derived tumour organoids compared with antigen-presentation-proficient cells. By comparing paired tumour samples from patients with MMR-d colon cancer that were obtained before and after dual PD-1 and CTLA-4 blockade, we found that immune checkpoint blockade substantially increased the frequency of γδ T cells in B2M-deficient cancers. Taken together, these data indicate that γδ T cells contribute to the response to immune checkpoint blockade in patients with HLA-class-I-negative MMR-d colon cancers, and underline the potential of γδ T cells in cancer immunotherapy. γδ T cells contribute to the response to immune checkpoint blockade treatment in patients with HLA-class-I-negative DNA mismatch repair-deficient colon cancers. .
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人肠道 Vdelta1+ 淋巴细胞识别上皮来源的肿瘤细胞。
影响因子：
15.3
作者：
Maeurer, MJ;Martin, D;Walter, W;Liu, KH;Zitvogel, L;Halusczcak, K;Rabinowich, H;Duquesnoy, R;Storkus, W;Lotze, MT
通讯作者：
Lotze, MT
影响因子：
45.3
作者：
Overman, Michael J.;Lonardi, Sara;Andre, Thierry
通讯作者：
Andre, Thierry
影响因子：
28.2
作者：
Germano, Giovanni;Lu, Steve;Bardelli, Alberto
通讯作者：
Bardelli, Alberto
影响因子：
17.1
作者：
Liu, Yuzhen;Horn, Jessie L.;Hsieh, Andrew C.
通讯作者：
Hsieh, Andrew C.
影响因子：
82.9
作者：
Cader, Fathima Zumla;Hu, Xihao;Goh, Walter L.;Wienand, Kirsty;Ouyang, Jing;Mandato, Elisa;Redd, Robert;Lawton, Lee N.;Chen, Pei-Hsuan;Weirather, Jason L.;Schackmann, Ron C. J.;Li, Bo;Ma, Wenjiang;Armand, Philippe;Rodig, Scott J.;Neuberg, Donna;Liu, X. Shirley;Shipp, Margaret A.
通讯作者：
Shipp, Margaret A.