Faculty of Medicine, Department of Immunology, University of Tsukuba, Tsukuba, Japan.
Faculty of Medicine, Breast and Endocrine Surgery, University of Tsukuba, Tsukuba, Japan.
Cancer Sci. 2022 Nov;113(11):4001-4004. doi: 10.1111/cas.15526. Epub 2022 Aug 30.
CD155 is a shared ligand for activating and inhibitory immunoreceptors DNAX accessory molecule 1 (DNAM-1), also called CD226, and T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT), which are expressed on natural killer (NK) cells and T cells, and positively and negatively regulates tumor immune responses, respectively. A recent study showed that the single nucleotide polymorphism rs1058402G>A causing a mutation to Thr from Ala at residue 67 of CD155 is associated with worse overall survival of patients with small cell lung cancer and suggested that this is caused by the decreased affinity of mutant CD155 for DNAM-1 as a result of the 3D structural analysis. Unexpectedly, however, we found that the mutation increased the binding affinity for TIGIT rather than decreased the binding affinity for DNAM-1 and induced a stronger signal than WT CD155. Our results suggest that the mutation suppresses tumor immune responses by generating a stronger inhibitory signal in immune cells in the tumor microenvironment.
CD155 是一种共享配体，可激活和抑制免疫受体 DNAX 辅助分子 1（DNAM-1），也称为 CD226，以及 T 细胞免疫球蛋白和免疫受体酪氨酸基抑制基序域（TIGIT），这些受体表达在自然杀伤（NK）细胞和 T 细胞上，并分别正向和负向调节肿瘤免疫反应。最近的一项研究表明，导致 CD155 残基 67 位 Thr 突变为 Ala 的单核苷酸多态性 rs1058402G>A 与小细胞肺癌患者的总生存期较差相关，并表明这是由于突变型 CD155 与 DNAM-1 的亲和力降低所致，这是通过 3D 结构分析得出的。然而，出乎意料的是，我们发现该突变增加了与 TIGIT 的结合亲和力，而不是降低了与 DNAM-1 的结合亲和力，并诱导了比 WT CD155 更强的信号。我们的结果表明，该突变通过在肿瘤微环境中的免疫细胞中产生更强的抑制信号来抑制肿瘤免疫反应。
