荷兰癌症研究所Emile E. Voest等研究人员合作发现，γδ T细胞是HLA I类缺陷型癌症免疫治疗的效应子。该研究于2023年1月11日在线发表于国际一流学术期刊《自然》。

与其他癌症类型相比，研究人员观察到21种错配修复缺陷（MMR-d）癌症中的20种（95%）具有β2-微球蛋白（由B2M编码）的基因组失活，并保留了对免疫检查点阻断（ICB）的反应性，表明在这种情况下，除CD8⁺T细胞外，免疫效应细胞也参与其中。研究人员接下来发现，在MMR-d癌症中，B2M失活与γδ T细胞浸润增加之间有密切的联系。这些γδ T细胞主要包括Vδ1和Vδ3亚群，并表达高水平的PD-1、其他激活标志物，包括细胞毒性分子和广泛的杀伤细胞免疫球蛋白样受体。在体外，从MMR-d结肠癌中分离出来的PD-1⁺γδ T细胞与抗原呈递功能健全的细胞相比，对人类白细胞抗原（HLA）-I类阴性的MMR-d结肠癌细胞系和B2M基因敲除患者衍生的肿瘤器官的反应性增强。

通过比较来自MMR-d结肠癌患者在PD-1和CTLA-4双重阻断前后的配对肿瘤样本，研究人员发现免疫检查点阻断大大增加了B2M缺陷型癌症中γδT细胞的频率。总之，这些数据表明，在HLA-I类阴性MMR-d结肠癌患者中，γδT细胞有助于对免疫检查点阻断的反应，并强调了γδT细胞在癌症免疫疗法中的潜力。

据介绍，DNA MMR-d的癌症呈现出大量的新抗原，这被认为是其对ICB有特殊反应的原因。

附：英文原文

Title: γδ T cells are effectors of immunotherapy in cancers with HLA class I defects

Author: 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.

Issue&Volume: 2023-01-11

Abstract: 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)1,2. Here, in contrast to other cancer types3,4,5, 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.

DOI: 10.1038/s41586-022-05593-1

Source: https://www.nature.com/articles/s41586-022-05593-1