Integrated germline and somatic features reveal divergent immune pathways driving ICB response

Immune Checkpoint Blockade (ICB) has revolutionized cancer treatment, however mechanisms determining patient response remain poorly understood. Here we used machine learning to predict ICB response from germline and somatic biomarkers and interpreted the learned model to uncover putative mechanisms driving superior outcomes. Patients with higher T follicular helper infiltrates were robust to defects in the class-I Major Histocompatibility Complex (MHC-I). Further investigation uncovered different ICB responses in MHC-I versus MHC-II neoantigen reliant tumors across patients. Despite similar response rates, MHC-II reliant responses were associated with significantly longer durable clinical benefit (Discovery: Median OS=63.6 vs. 34.5 months P=0.0074; Validation: Median OS=37.5 vs. 33.1 months, P=0.040). Characteristics of the tumor immune microenvironment reflected MHC neoantigen reliance, and analysis of immune checkpoints revealed LAG3 as a potential target in MHC-II but not MHC-I reliant responses. This study highlights the value of interpretable machine learning models in elucidating the biological basis of therapy responses. Statement of SignificanceImmune checkpoint blockade works only in a fraction of patients for reasons that are still not fully understood. Our study reveals heterogeneity in the immune responses of ICB responders that correlates with characteristics of the neoantigen landscape. This heterogeneity is accompanied by differences in the duration of clinical benefit as well as by differences as to which immune checkpoint gene serves as a biomarker of ICB response. These findings suggest possible new strategies for improving ICB responses. HighlightsO_LIWe used machine learning to study ICB response across 708 patients from 8 studies across 3 tumor types (melanoma, RCC, and NSCLC). C_LIO_LICombining germline and somatic features improves prediction of ICB response C_LIO_LIInteractions between germline and somatic features reveal mechanisms contributing to ICB sensitivity. C_LIO_LIMHC-I vs. MHC-II reliance implicates LAG3 as a prognostic biomarker in the context of CD4 T cell driven responses. C_LIO_LIMHC-II neoantigen reliant responses provide superior durable clinical benefit in response to ICB. C_LI