IL7 Genetic Variation Predicts Immune-Related Adverse Events

Immunotherapy, especially use of immune checkpoint inhibitors (ICI), has revolutionized cancer treatment, but immune-related adverse events (irAE) are common and can lead to subsequent cessation of therapy. Germline genetic determinants have been postulated to impact the severity of irAEs; however, genetic variants that are reproducibly associated with irAEs have not been identified. In two complementary studies, Groha and colleagues along with Taylor, Watson, Tong, and colleagues sought to determine individual genetic risk factors for developing irAEs after ICI treatment and revealed a notable association between increased risk of severe irAEs and carriers of the rs16906115 minor allele, which is intronic to IL7. Groha and colleagues conducted a genome-wide association study (GWAS) of 1,751 patients treated with ICIs across 12 cancer types and identified three associations at GWAS significance: rs16906115 intronic IL7, rs75824728 near IL22RA1, and rs113861051 on 4p15, with rs16906115 being replicated in three independent studies. Individuals that carry the minor rs16906115 allele had enhanced lymphocyte stability after immunotherapy, with this variant also being shown to initiate a new cryptic isoform of IL7 that is a critical regulator of lymphocyte homeostasis. Similar outcomes were observed in the study by Taylor, Watson, Tong, and colleagues, in which, studying 214 patients treated with ICIs for melanoma, it was revealed by single-cell RNA sequencing of B cells that risk-allele carriers of rs16906115 have increased pretreatment B-cell IL7 expression, which was independently associated with irAE risk, indicating causality. This group also showed that risk allele carriers have distinct CD8⁺ T-cell responses induced by ICI treatment, which contributes to skewed T-cell clonality and a greater proportional repertoire occupancy by larger clones. Notably, both studies also indicated that the rs16906115 risk allele could be predictive of survival in untreated patients. Together, the results of these two studies indicate that rs16906115 allele status is associated with irAEs after ICI treatment, implicating both IL7 and B cells in the ICI response, and provides a potential predictor for both irAE risk and survival outcomes in cancer.

Groha S, Alaiwi SA, Xu W, Naranbhai V, Nassar AH, Bakouny Z, et al. Germline variants associated with toxicity to immune checkpoint blockade. Nat Med 2022;28:2584–91.

Taylor CA, Watson RA, Tong O, Ye W, Nassiri I, Gilchrist JJ, et al. IL7 genetic variation and toxicity to immune checkpoint blockade in patients with melanoma. Nat Med 2022;28:2592–600.

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