摘要：SummaryCD8+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.Graphical abstractDisplay OmittedHighlights•HLA homozygosity reduces antigen coverage and is associated with earlier tumor onset•Tumors with VHL−/−, such as ccRCC, have the opposite association•In VHL−/−tumors, CD8+T cell immunity may have adverse effects in imunosurveillanceImmunology; Components of the immune system; Cancer
