Germline genomes have a dominant-heritable contribution to cancer immune evasion and immunotherapy response
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REVIEW Germline genomes have a dominant-heritable contribution to cancer immune evasion and immunotherapy response Xue Jiang1,†, Mohammad Asad2,†, Lin Li2, Zhanpeng Sun2,3, Jean-Sébastien Milanese4, Bo Liao5,*, Edwin Wang2,* 1
Shanghai Mental Health Center, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, T2N 4N1, Canada 3 Tianjin Normal University, Tianjin 300074, China 4 Human Health Therapeutics Research Centre, National Research Council Canada, Montreal, H4P 2R2, Canada 5 School of Mathematics and Statistics, Hainan Normal University, Haikou 570206, China * Correspondence: [email protected], [email protected] 2
Received January 22, 2020; Revised March 28, 2020; Accepted April 30, 2020 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 tumorimmunity system’s complexity. In the past, germline pathogenic variants have been thought to have only minorheritable 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. Conclusions: 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.
Keywords: germline; genomics; cancer; immune evasion; immunotherapy response Author summary: Traditionally, it has been believed that germline pathogenic variants and family histories explain 5%–10% of cancer patient population, thus, heredity has been suggested to have a small contribution to tumorigenesis and metastasis. However, the host immune system often interacts with cancer cells, therefore, escaping from the host immune system surveillance is one of the critical means for tumorigenesis. In the past a few ye
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