Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy
Menée à partir de données cliniques et génomiques portant sur 1 535 patients atteints d'un cancer de stade avancé, cette étude met en évidence une association entre les caractéristiques du génotype HLA-I des patients et la réponse à une immunothérapie par inhibiteur de point de contrôle (anti-PD1 ou anti-CTLA-4)
CD8+ T cell-dependent killing of cancer cells requires efficient presentation of tumor antigens by human leukocyte antigen class I (HLA-I) molecules. However, the extent to which patient-specific HLA-I genotype influences response to anti-PD-1 or anti-CTLA-4 is currently unknown. We determined the HLA-I genotype of 1,535 advanced cancer patients treated with immune checkpoint blockade (ICB). Maximal heterozygosity at HLA-I loci (A, B, and C) improved overall survival after ICB compared to patients who were homozygous for at least one HLA locus. In two independent melanoma cohorts, patients with the HLA-B44 supertype had extended survival, whereas the HLA-B62 supertype (including HLA-B*15:01) or somatic loss of heterozygosity at HLA-I, was associated with poor outcome. Molecular dynamics simulations of HLA-B*15:01 revealed unique elements that may impair CD8+ T cell recognition of neoantigens. Our results have important implications for predicting response to ICB and for the design of neoantigen-based therapeutic vaccines.
Science , résumé, 2016