Genetic mechanisms of HLA-I loss and immune escape in diffuse large B cell lymphoma

Significance Fifty percent of diffuse large B cell lymphoma (DLBCL) evade immune-surveillance via somatic genetic lesions abrogating the expression of the class I major histocompatibility complex (MHC-I) complex on the cell surface, thus preventing the presentation of tumor neoantigens to the immune system. The results herein significantly extend these findings by showing that an additional 40% of DLBCL cases, despite expressing MHC-I, carry monoallelic HLA-I genetic alterations that limit the repertoire of neoantigens for presentation to immune cells. Both MHC-I NEG and MHC-I POS /monoallelically disrupted cases have significantly higher mutational load. Notably, homozygosis of HLA-I loci is significantly and preferentially enriched in the germline of DLBCL patients, suggesting a stepwise process by which limited neoantigen presentation is selected during DLBCL development.