iScience (Jun 2022)

HLA-I-restricted CD8+ T cell immunity may accelerate tumorigenesis in conjunction with VHL inactivation

  • BeumJin Park,
  • Seok-Jae Heo,
  • Yong Joon Lee,
  • Mi-Kyoung Seo,
  • Jiyun Hong,
  • Eui-Cheol Shin,
  • Inkyung Jung,
  • Sangwoo Kim

Journal volume & issue
Vol. 25, no. 6
p. 104467

Abstract

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Summary: 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.

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