Autoimmune Alleles at the Major Histocompatibility Locus Modify Melanoma Susceptibility
By
James Talwar,
David Laub,
Meghana Pagadala,
Andrea Castro,
McKenna Lewis,
Georg E. Luebeck,
Bryan Gorman,
Cuiping Pan,
Frederick N. Dong,
Kyriacos Markianos,
Richard Hauger,
Saiju Pyarajan,
Philip S. Tsao,
Gerald P. Morris,
Rany M. Salem,
Wesley K Thompson,
Kit Curtius,
Maurizio Zanetti,
Hannah W Carter
Posted 13 Aug 2021
bioRxiv DOI: 10.1101/2021.08.12.456166
Autoimmunity and cancer represent two different aspects of immune dysfunction. Autoimmunity is characterized by breakdowns in immune self-tolerance, while impaired immune surveillance can allow for tumorigenesis. The class I major histocompatibility complex (MHC-I), which displays derivatives of the cellular peptidome for immune surveillance by CD8+ T cells, serves as a common genetic link between these conditions. As melanoma-specific CD8+ T-cells have been shown to target melanocyte-specific peptide antigens more often than melanoma-specific antigens, we investigated whether vitiligo and psoriasis predisposing MHC-I alleles conferred a melanoma protective effect. In individuals with cutaneous melanoma from both The Cancer Genome Atlas (N = 451) and an independent validation cohort (N = 586), MHC-I autoimmune allele carrier status was significantly associated with a later age of melanoma diagnosis. Furthermore, MHC-I autoimmune allele carriers were significantly associated with decreased risk of developing melanoma in the Million Veterans Program cohort (OR = 0.962, p = 0.024). Existing melanoma polygenic risk scores (PRS) did not predict autoimmune allele carrier status, suggesting these alleles provide new risk-relevant information. Mechanisms of autoimmune protection were neither associated with improved melanoma-driver mutation association nor improved gene-level conserved antigen presentation relative to common alleles (population frequency > 1%). However, autoimmune alleles showed higher affinity relative to common alleles for particular windows of melanocyte conserved antigens suggesting a potential relationship between antigen processing, binding, and cell-surface presentation. Overall, this study presents evidence that MHC-I autoimmune risk alleles modulate melanoma risk unaccounted for by current PRS.
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