Germline variants associated with toxicity to immune checkpoint blockade

Area of Science:

• Immunology
• Genetics
• Oncology

Background:

• Immune checkpoint inhibitors (ICIs) are effective cancer treatments but can cause immune-related adverse events (irAEs).
• The genetic basis for irAE susceptibility is largely unknown, hindering personalized treatment strategies.
• Previous studies hypothesized germline predispositions to irAEs, but no specific variants were identified.

Purpose of the Study:

• To identify germline genetic variants associated with the development of irAEs in patients receiving ICIs.
• To investigate the relationship between genetic factors, irAE occurrence, and patient outcomes.

Main Methods:

• A genome-wide association study (GWAS) was conducted on 1,751 patients across 12 cancer types treated with ICIs.
• Two irAE phenotypes were analyzed: high-grade (3-5) and all-grade events.
• Significant associations were identified and validated in independent cohorts.

Main Results:

• Three genome-wide significant associations with all-grade irAEs were found near IL7, IL22RA1, and on chromosome 4p15.
• The variant rs16906115 near IL7 was robustly replicated and associated with a gain of a cryptic exon.
• Patients with the IL7 variant showed enhanced lymphocyte stability post-ICI initiation, predicting irAEs and improved survival.

Conclusions:

• Germline variants, particularly near IL7, are associated with irAE risk in patients treated with ICIs.
• The IL7 variant's association with lymphocyte stability suggests a mechanism for irAE development.
• These findings offer potential biomarkers for predicting irAEs and may inform patient stratification for ICI therapy.