| Autor: |
Benjamin Fairfax, Chelsea Taylor, Robert Watson, Orion Tong, Weiyu Ye, Isar Nassiri, James Gilchrist, Alba Verge de los Aires, Piyush Sharma, Surya Koturan, Rosalin Cooper, Victoria Woodcock, Elsita Jungkurth, Brian Shine, Nicholas Coupe, Miranda Payne, Vivek Naranbhai, Stefan Groha, Paul Emery, Kulveer Mankia, Matthew Freedman, Toni Choueiri, M Middleton, Alexander Gusev |
| Rok vydání: |
2022 |
| Popis: |
Although treatment with immune checkpoint blockade (ICB) has transformed outcomes for patients with melanoma (1, 2), it frequently triggers immune related adverse events (irAEs), causing serious morbidity and presenting a major hurdle to immuno-oncology (3, 4). The degree to which germline genetic variation predisposes to irAEs is unknown. Here, studying a cohort of 214 patients receiving ICB for melanoma, we observe increased risk of severe irAEs in carriers of the minor allele of rs16906115, intronic to IL7. We find rs16906115 forms a B cell specific expression quantitative trait locus to IL7 in patients only, with risk allele carriers demonstrating increased B cell IL7 expression, immunoglobulin class switching and somatic hypermutation. Notably, increased B cell IL7 expression is independently associated with risk of irAEs. Consistent with the role of IL-7 in T cell development, risk allele carriers have distinct ICB induced CD8+ T cell subset responses, with allelic effects on gene expression and clonality. Risk allele carriers display significantly reduced CD8+ T cell mitotic responses to ICB, with skewing of T cell clonality and increased counts of large clones previously associated with disease response. These observations highlight key roles for both B cells and IL-7 in ICB response and toxicity, and demonstrate the power of agnostic human genetic studies to reveal novel determinants of response to cancer immunotherapy. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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