Germline genomes have a dominant-heritable contribution to cancer immune evasion and immunotherapy response

Abstract

Background: Immune evasion is a fundamental hallmark for cancer. At the early stages of tumor development, immune evasion strategies must be implemented by tumors to prevent attacks from the host immune systems. Blocking tumors’ immune evasion will re-activate the host immune systems to eliminate tumors. Immune-checkpoint therapy (ICT) which applies anti-PD-1/PD-L1 or anti-CTLA4 treatment has been a remarkable success in the past few years. However, ~70% of patients cannot gain any clinical benefits from ICT treatment due to the tumor-immunity system’s complexity. In the past, germline pathogenic variants have been thought to have only minor-heritable contributions to cancer.

Results: Emerging evidence has shown that germline genomes play a dominant-heritable contribution to cancer via encoding the host immune system. The functional components of the immune system are encoded by the host genome, thus the germline genome might have a profound impact on cancer immune evasion and immunotherapy response. Indeed, recent studies showed that germline pathogenic variants can influence immune capacity in cancer patients at a population level by (i) shaping tumor somatic mutations, altering methylation patterns and antigen-presentation capacity or (ii) influencing NK cell’s function to modulate lymphocyte infiltration in the tumor microenvironment. In addition, the HLA (types A, B or C) genotypes also shape the landscape of tumor somatic mutations.

Conclusion: These results highlight the indispensable roles of germline genome in immunity and cancer development and suggest that germline genomics should be integrated into the research field of cancer biology and cancer immunotherapy.

Graphical abstract

Keywords

germline / genomics / cancer / immune evasion / immunotherapy response

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