Integrative analysis of risk factors for immune-related adverse events of checkpoint blockade therapy in cancer

Abstract

Immune-related adverse events (irAEs) related to checkpoint inhibitors should involve a multitude of different risk factors. To delineate the multifaceted complexity of the underlying mechanisms, I compiled germline exomes and blood transcriptomes together with clinical and laboratory data for samples before and after checkpoint treatment in 385 various irAE cases and 300 controls. Overall, irAE cases showed limited neutrophil function in terms of baseline cell count and on-therapy gene activation. Allelic and copy number variation of HLA-B genes correlated with the risk of particular irAEs. Based on integrative modeling for risk prediction, I mapped germline coding variants to different irAE phenotypes. In particular, I identified a nonsense variant in TMEM162. Integration with our cohort and TCGA data revealed its association with an increase in B cells and a decrease in regulatory T cells in both peripheral blood and tumor. These results shed new insights into underlying factors of irAE risk.