Park BeumJin, Heo Seok-Jae, Lee Yong Joon, Seo Mi-Kyoung, Hong Jiyun, Shin Eui-Cheol, Jung Inkyung, Kim Sangwoo
Department of Biomedical Systems Informatics and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.
Division of Biostatistics, Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Korea.
iScience. 2022 May 25;25(6):104467. doi: 10.1016/j.isci.2022.104467. eCollection 2022 Jun 17.
CD8 T cells recognize and kill tumor cells with HLA-I tumor antigens in early tumorigenesis, the efficiency of which differs according to antigen-recognition coverage, as shown in earlier tumor onset in HLA-I homozygosity. However, the universality of these associations remains unknown. Here, we assessed the tumor type and driver mutation specificity in the association between tumor onset age and HLA-I zygosity. Statistical analyses identified an unexpected negative relationship in tumors with VHL biallelic loss, wherein HLA-I heterozygosity was associated with earlier tumor onset, while all others showed either no or a positive association. Testing on an independent dataset reproduced the VHL-dependent acceleration of tumor onset in the HLA-I heterozygous group, confirming the association. Further speculation proposed VEGF-A-mediated T cell exhaustion under VHL inactivation as a potential mechanism. Our findings suggest that CD8 T cell immunity in early tumor suppression can be conditional to the genetic status of tumors and may even lead to adverse consequences.
CD8 T细胞在肿瘤发生早期识别并杀死带有HLA-I肿瘤抗原的肿瘤细胞，其效率根据抗原识别覆盖范围而有所不同，如HLA-I纯合性导致的肿瘤发病较早所显示的那样。然而，这些关联的普遍性仍然未知。在此，我们评估了肿瘤发病年龄与HLA-I杂合性之间关联中的肿瘤类型和驱动突变特异性。统计分析在伴有VHL双等位基因缺失的肿瘤中发现了意外的负相关关系，其中HLA-I杂合性与较早的肿瘤发病相关，而其他所有肿瘤要么无关联，要么呈正相关。在独立数据集上的测试重现了HLA-I杂合组中依赖VHL的肿瘤发病加速情况，证实了这种关联。进一步推测提出，VHL失活状态下VEGF-A介导的T细胞耗竭是一种潜在机制。我们的研究结果表明，早期肿瘤抑制中的CD8 T细胞免疫可能取决于肿瘤的基因状态，甚至可能导致不良后果。
