A Genome-Wide Association Study of irAEs Identifies New Genome-Wide Significant Associations in An Observational Pancancer Setting

Findings from a genome-wide association study (GWAS) conducted among 1751 patients treated with immune checkpoint inhibitors (ICIs) across 12 cancer types demonstrate that a variant of the IL7 gene predicts the toxicity of ICIs in patients with cancer, via a mechanism shared with autoimmune diseases, a finding which could inform biomarker and treatment strategies in both of these contexts. In particular, patients carrying the IL7 germline variant exhibited significantly increased lymphocyte stability after ICI initiation, which was itself predictive of downstream immune-related adverse events (irAEs) and improved survival. Although the study team focused this work on the mechanistic follow-up of IL7 due to its consistent replication, the independent associations near IL22RA1 and 4p15 may pinpoint additional mechanisms. The results are published by Dr. Alexander Gusev of the Division of Population Sciences, Department of Medical Oncology, Dana-Farber Cancer Institute in Boston, MA, USA, Broad Institute of Harvard & MIT in Cambridge, MA, USA, Harvard Medical School in Boston, and Division of Genetics, Brigham and Women’s Hospital in Boston, MA, USA and colleagues on 16 December 2022 in the Nature Medicine.

The authors wrote in the background that ICIs revolutionised cancer care, but treatment can also affect non-malignant tissues and cause autoimmune-like side effects. Patients treated with ICIs commonly experience irAEs. High-grade irAEs can lead to hospitalisation and treatment cessation in 15–30% of patients, emphasizing the urgent need to understand the mechanisms and predictors of irAEs. Recent studies have also shown that irAEs correlate with positive anticancer responses, highlighting their relevance to broader treatment outcomes.

One hypothesis for the heterogeneity in irAE onset and severity is the impact of germline genetic determinants of immune activity. Recent work has shown that polygenic germline risk for autoimmune conditions is correlated with the onset of cutaneous and thyroid irAEs. Previous studies of response to ICIs have also highlighted both individual germline human leukocyte antigen alleles and major histocompatibility complex diversity as predictors of overall survival.

Although germline causes for irAEs have been hypothesized, no individual variant associated with developing irAEs has been identified. In this work, the investigators hypothesized that individual germline variants may influence the broad spectrum of irAEs by modulating the general excitability of the immune system, as recently observed for somatic alterations. They carried out a GWAS of irAEs for patients on ICIs at a single institution, followed by replication in patients treated at an independent institution and on clinical studies.

The study team in particular investigated two irAE phenotypes, high grade (3–5) and all grade events. They identified 3 genome-wide significant associations (p < 5×10−8) in the discovery cohort associated with all grade irAEs: rs16906115 near IL7 (combined p = 3.6×10−11; hazard ratio [HR) 2.1); rs75824728 near IL22RA1 (combined p = 3.5×10−8; HR 1.8); and rs113861051 on 4p15 (combined p = 1.2×10−8, HR 2.0); rs16906115 was replicated in 3 independent studies.

The association near IL7 colocalised with the gain of a new cryptic exon for IL7, a critical regulator of lymphocyte homeostasis. Patients carrying the IL7 germline variant exhibited significantly increased lymphocyte stability after ICI initiation, which was itself predictive of downstream irAEs and improved survival.

The authors concluded that their GWAS study of irAEs, conducted in an observational pancancer setting, identified three new genome-wide significant associations, with replication of a variant near IL7 in three independent cohorts. This variant appeared to initiate a new cryptic isoform of IL7, was predictive of lymphocyte stability in patients on ICIs and improved prognosis in TCGA melanoma, which is predominantly a cohort not on ICIs. Furthermore, the independent associations near IL22RA1 and 4p15 may pinpoint additional mechanisms.

In terms of relevance of these findings, the authors commented that the identification of genetic variants associated with irAEs is consistent with a hypothesized patient-specific immunological set point and opens avenues for future analysis to inform the genetic architecture of irAEs. Larger studies will enable polygenic analyses to uncover the cell types, gene sets and pathways that drive these outcomes. The utility of these associations to identify high-risk patients for monitoring or treatment modifications must be evaluated in prospective, randomised studies in conjunction with their influence on antitumour response.

Following authors Matthew L. Freedman, Toni K. Choueiri, and Alexander Gusev contributed equally.

Reference

Groha S, Alaiwi SA, Xu W, et al. Germline variants associated with toxicity to immune checkpoint blockade. Nature Medicine 2022; 28:2584-2591. DOI: https://doi.org/10.1038/s41591-022-02094-6

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