Genetic mechanisms of HLA-I loss and immune escape in diffuse large B cell lymphoma
Marco Fangazio, Erik Ladewig, Karen Gomez, Laura Garcia‐Ibanez, Rahul Kumar, Julie Teruya‐Feldstein, Davide Rossi, Ioan Filip, Qiang Pan‐Hammarström, Giorgio Inghirami, Renzo Boldorini, German Ott, Annette M. Staiger, Bjoern Chapuy, Gianluca Gaïdano, Govind Bhagat, Katia Basso, Raúl Rabadán, Laura Pasqualucci, Riccardo Dalla‐Favera
Abstract
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.