Genetic variation associated with thyroid autoimmunity shapes the systemic immune response to PD-1 checkpoint blockade

Abstract

Activation of systemic immune responses using PD-1 checkpoint inhibitors is an essential approach to cancer therapy. Yet, the extent of benefit relative to risk of immune related adverse events (irAE) varies widely among patients. Here, we study endocrine irAE from 7 clinical trials across 6 cancers where atezolizumab (anti-PD-L1) was combined with chemotherapies and compared to standard of care. We show that atezolizumab-induced thyroid dysfunction is associated with longer survival. We construct a polygenic risk score (PRS) for lifetime risk of hypothyroidism using a GWAS from the UK Biobank and apply this PRS to genetic data collected from 2,616 patients of European ancestry from these trials. Patients with high PRS are at increased risk of atezolizumab-induced thyroid dysfunction and lower risk of death in triple negative breast cancer. Our results indicate that genetic variation associated with thyroid autoimmunity interacts with biological pathways driving the systemic immune response to PD-1 blockade.

Germline variants associated with immunotherapy-related adverse events

“…Ethics Committees (EC) and Institutional Review Boards (IRB) at each study site for each clinical trial approved the clinical trial protocol, the main study ICF, and the RBR ICF. Whole-genome sequencing data was collected from whole blood (as previously described 9 ) and used to compute individual variant association statistics.…”

“…A subset of patients signed an optional Research Biosample Repository (RBR) Informed Consent Form (ICF) to provide whole blood samples for future research, including study of inherited and non-inherited genetic variation from these whole blood samples. Whole-genome sequencing data was collected from whole blood as previously described 9 . Genetic ancestry was inferred using ADMIXTURE and restricted to Europeans (ancestry >0.7).…”

“…One hypothesis for the heterogeneity in irAE onset and severity is the impact of germline genetic determinants of immune activity 6 . Recent work has shown that polygenic germline risk for autoimmune conditions is correlated with onset of cutaneous and thyroid irAEs 9,10 . Prior studies of response to ICIs have also highlighted both individual germline HLA alleles 11 and MHC diversity 12 as predictors of overall survival.…”

Immune Related Adverse Events of the Thyroid – A Narrative Review

“…Genetic factors associated with lifetime risk of autoimmune thyroid disease have been implicated in the risk of developing thyroid irAEs during ICI-treatment ( 21 , 22 ). Key loci have been implicated from genes regulating the immune response such as CD69 (T-cell activation), LPP (B-cell maturation), CTLA-4 (T-cell priming) and PTPN22 (T-cell and B-cell receptor signaling).…”

“…Key loci have been implicated from genes regulating the immune response such as CD69 (T-cell activation), LPP (B-cell maturation), CTLA-4 (T-cell priming) and PTPN22 (T-cell and B-cell receptor signaling). When these genes and others are combined into a polygenic risk score they can identify subgroups of patients at >6-fold increased risk of thyroid irAEs and identify patients at a lower risk of cancer death ( 21 ).…”