IL7 genetic variation and toxicity to immune checkpoint blockade in patients with melanoma
<p>Treatment with immune checkpoint blockade (ICB) frequently triggers immune-related adverse events (irAEs), causing considerable morbidity. In 214 patients receiving ICB for melanoma, we observed increased severe irAE risk in minor allele carriers of rs16906115, intronic to <em&g...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Springer Nature
2022
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| _version_ | 1797109515852709888 |
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| author | Taylor, CA Watson, RA Tong, O Ye, W Nassiri, I Gilchrist, JJ de Los Aires, AV Sharma, PK Koturan, S Cooper, RA Woodcock, VK Jungkurth, E Shine, B Coupe, N Payne, MJ Church, DN Naranbhai, V Groha, S Emery, P Mankia, K Freedman, ML Choueiri, TK Middleton, MR Gusev, A Fairfax, BP |
| author_facet | Taylor, CA Watson, RA Tong, O Ye, W Nassiri, I Gilchrist, JJ de Los Aires, AV Sharma, PK Koturan, S Cooper, RA Woodcock, VK Jungkurth, E Shine, B Coupe, N Payne, MJ Church, DN Naranbhai, V Groha, S Emery, P Mankia, K Freedman, ML Choueiri, TK Middleton, MR Gusev, A Fairfax, BP |
| author_sort | Taylor, CA |
| collection | OXFORD |
| description | <p>Treatment with immune checkpoint blockade (ICB) frequently triggers immune-related adverse events (irAEs), causing considerable morbidity. In 214 patients receiving ICB for melanoma, we observed increased severe irAE risk in minor allele carriers of rs16906115, intronic to <em>IL7</em>. We found that rs16906115 forms a B cell-specific expression quantitative trait locus (eQTL) to <em>IL7</em> in patients. Patients carrying the risk allele demonstrate increased pre-treatment B cell <em>IL7</em> expression, which independently associates with irAE risk, divergent immunoglobulin expression and more B cell receptor mutations. Consistent with the role of IL-7 in T cell development, risk allele carriers have distinct ICB-induced CD8<sup>+</sup> T cell subset responses, skewing of T cell clonality and greater proportional repertoire occupancy by large clones. Finally, analysis of TCGA data suggests that risk allele carriers independently have improved melanoma survival. These observations highlight key roles for B cells and IL-7 in both ICB response and toxicity and clinical outcomes in melanoma.</p> |
| first_indexed | 2024-03-07T07:42:49Z |
| format | Journal article |
| id | oxford-uuid:a9d2effb-84ee-44fa-bfc8-517c9db4a5ae |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:42:49Z |
| publishDate | 2022 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:a9d2effb-84ee-44fa-bfc8-517c9db4a5ae2023-05-05T08:09:31ZIL7 genetic variation and toxicity to immune checkpoint blockade in patients with melanomaJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:a9d2effb-84ee-44fa-bfc8-517c9db4a5aeEnglishSymplectic ElementsSpringer Nature2022Taylor, CAWatson, RATong, OYe, WNassiri, IGilchrist, JJde Los Aires, AVSharma, PKKoturan, SCooper, RAWoodcock, VKJungkurth, EShine, BCoupe, NPayne, MJChurch, DNNaranbhai, VGroha, SEmery, PMankia, KFreedman, MLChoueiri, TKMiddleton, MRGusev, AFairfax, BP<p>Treatment with immune checkpoint blockade (ICB) frequently triggers immune-related adverse events (irAEs), causing considerable morbidity. In 214 patients receiving ICB for melanoma, we observed increased severe irAE risk in minor allele carriers of rs16906115, intronic to <em>IL7</em>. We found that rs16906115 forms a B cell-specific expression quantitative trait locus (eQTL) to <em>IL7</em> in patients. Patients carrying the risk allele demonstrate increased pre-treatment B cell <em>IL7</em> expression, which independently associates with irAE risk, divergent immunoglobulin expression and more B cell receptor mutations. Consistent with the role of IL-7 in T cell development, risk allele carriers have distinct ICB-induced CD8<sup>+</sup> T cell subset responses, skewing of T cell clonality and greater proportional repertoire occupancy by large clones. Finally, analysis of TCGA data suggests that risk allele carriers independently have improved melanoma survival. These observations highlight key roles for B cells and IL-7 in both ICB response and toxicity and clinical outcomes in melanoma.</p> |
| spellingShingle | Taylor, CA Watson, RA Tong, O Ye, W Nassiri, I Gilchrist, JJ de Los Aires, AV Sharma, PK Koturan, S Cooper, RA Woodcock, VK Jungkurth, E Shine, B Coupe, N Payne, MJ Church, DN Naranbhai, V Groha, S Emery, P Mankia, K Freedman, ML Choueiri, TK Middleton, MR Gusev, A Fairfax, BP IL7 genetic variation and toxicity to immune checkpoint blockade in patients with melanoma |
| title | IL7 genetic variation and toxicity to immune checkpoint blockade in patients with melanoma |
| title_full | IL7 genetic variation and toxicity to immune checkpoint blockade in patients with melanoma |
| title_fullStr | IL7 genetic variation and toxicity to immune checkpoint blockade in patients with melanoma |
| title_full_unstemmed | IL7 genetic variation and toxicity to immune checkpoint blockade in patients with melanoma |
| title_short | IL7 genetic variation and toxicity to immune checkpoint blockade in patients with melanoma |
| title_sort | il7 genetic variation and toxicity to immune checkpoint blockade in patients with melanoma |
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