333HLA class II Immunogenic Mutation Burden Predicts Response to Immune Checkpoint Blockade
Menée à partir de données de séquençage portant sur 233 patients atteints d'un mélanome ou d'un cancer du poumon non à petites cellules, cette étude met en évidence une association entre la charge mutationnelle au niveau des gènes du complexe majeur d'histocompatibilité de classe II et la réponse aux inhibiteurs de points de contrôle immunitaire
Background : While HLA class I mutation-associated neoantigen burden has been linked with response to immune checkpoint blockade (ICB), the role of HLA class II restricted neoantigens in clinical responses to ICB is less studied. We used computational approaches to assess HLA class II immunogenic mutation (IMM) burden in patients with melanoma and lung cancer treated with ICB.
Patients and methods : We analyzed whole-exome sequence data from four cohorts of ICB-treated patients with melanoma (n=110) and non-small cell lung cancer (n=123). MHCnuggets, a neural network-based model, was applied to estimate HLA class II IMM burdens and cellular fractions of IMMs were calculated to assess mutation clonality. We evaluated the combined impact of HLA class II germline genetic variation and class II IMM burden on clinical outcomes. Correlations between HLA class II IMM burden and density of tumor infiltrating lymphocytes were computed from expression data.
Results : Responding tumors harbored a significantly higher HLA class II IMM burden for both melanoma and non-small cell lung cancer (P≤9.6e-3). HLA class II IMM burden was correlated with longer survival, particularly in the non-small cell lung cancer cohort and in the context of low intra-tumoral IMM heterogeneity (P<0.001). HLA class I and II IMM landscapes were largely distinct suggesting a complementary role for class II IMMs in tumor rejection. A higher HLA class II IMM burden was associated with CD4+ T-cell infiltration and PD-L1 expression. Transcriptomic analyses revealed an inflamed tumor microenvironment for tumors harboring a high HLA class II IMM burden.
Conclusions : HLA class II IMM burden identified patients with NSCLC and melanoma that attained longer survival after ICB treatment. Our findings suggest that HLA class II IMMs may impact responses to ICB in a manner that is distinct and complementary to HLA class I-mediated responses.
Annals of Oncology , résumé, 2022