Integrative analysis of risk factors for immune-related adverse events of checkpoint blockade therapy in cancer.
Nat Cancer
; 4(6): 844-859, 2023 06.
Article
en En
| MEDLINE
| ID: mdl-37308678
ABSTRACT
Immune-related adverse events (irAEs) induced by checkpoint inhibitors involve a multitude of different risk factors. Here, to interrogate the multifaceted underlying mechanisms, we compiled germline exomes and blood transcriptomes with clinical data, before and after checkpoint inhibitor treatment, from 672 patients with cancer. Overall, irAE samples showed a substantially lower contribution of neutrophils in terms of baseline and on-therapy cell counts and gene expression markers related to neutrophil function. Allelic variation of HLA-B correlated with overall irAE risk. Analysis of germline coding variants identified a nonsense mutation in an immunoglobulin superfamily protein, TMEM162. In our cohort and the Cancer Genome Atlas (TCGA) data, TMEM162 alteration was associated with higher peripheral and tumor-infiltrating B cell counts and suppression of regulatory T cells in response to therapy. We developed machine learning models for irAE prediction, validated using additional data from 169 patients. Our results provide valuable insights into risk factors of irAE and their clinical utility.
Texto completo:
1
Colección:
01-internacional
Asunto principal:
Enfermedades del Sistema Inmune
/
Neoplasias
Tipo de estudio:
Etiology_studies
/
Prognostic_studies
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Risk_factors_studies
Límite:
Humans
Idioma:
En
Revista:
Nat Cancer
Año:
2023
Tipo del documento:
Article