Abstract
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 IL7. We found that rs16906115 forms a B cell-specific expression quantitative trait locus (eQTL) to IL7 in patients. Patients carrying the risk allele demonstrate increased pre-treatment B cell IL7 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+ 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.
| Original language | English |
|---|---|
| Pages (from-to) | 2592-2600 |
| Number of pages | 9 |
| Journal | Nature Medicine |
| Volume | 28 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - Dec 2022 |
| Externally published | Yes |
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In: Nature Medicine, Vol. 28, No. 12, 12.2022, p. 2592-2600.
Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - IL7 genetic variation and toxicity to immune checkpoint blockade in patients with melanoma
AU - Taylor, Chelsea A.
AU - Watson, Robert A.
AU - Tong, Orion
AU - Ye, Weiyu
AU - Nassiri, Isar
AU - Gilchrist, James J.
AU - de los Aires, Alba Verge
AU - Sharma, Piyush Kumar
AU - Koturan, Surya
AU - Cooper, Rosalin A.
AU - Woodcock, Victoria K.
AU - Jungkurth, Elsita
AU - Shine, Brian
AU - Coupe, Nicholas
AU - Payne, Miranda J.
AU - Church, David N.
AU - Naranbhai, Vivek
AU - Groha, Stefan
AU - Emery, Paul
AU - Mankia, Kulveer
AU - Freedman, Matthew L.
AU - Choueiri, Toni K.
AU - Middleton, Mark R.
AU - Gusev, Alexander
AU - Fairfax, Benjamin P.
N1 - Funding Information: We are very grateful to all patients who contributed samples and participated in the study. We thank all the staff of the Day Treatment Unit, Oxford Cancer Centre and the Brodey Centre at the Horton General Hospital. We are grateful to all the staff of the Oxford University Hospitals NHS Foundation Trust haematology and biochemistry laboratory and thank T. James for his facilitation, as well as the staff of the Oxford Radcliffe Biobank and Churchill Hospital Sample Handling Lab. This study was funded by a Wellcome Intermediate Clinical Fellowship to B.P.F. (no. 201488/Z/16/Z), additionally supporting A.V.A. and I.N. R.A.W. is funded by a Wellcome Trust Doctoral Training Fellowship (no. BST00070). O.T. is supported by the Clarendon Fund, St. Edmund Hall and an Oxford Australia Scholarship. W.Y. is an NIHR academic clinical fellow and is supported by a CRUK predoctoral fellowship (reference RCCTI\100019). R.C. was supported by a CRUK Clinical Research Training Fellowship (S_3578). C.A.T. was funded by the Engineering & Physical Sciences Research Council and the Balliol Jowett Society (no. D4T00070). D.C. is funded by a Cancer Research UK Advanced Clinician Scientist Fellowship (C26642/A27963). J.J.G. is supported by an NIHR Clinical Lectureship. M.R.M. and B.P.F. are supported by the NIHR Oxford Biomedical Research Centre. K.M. and P.E. are supported by the NIHR Leeds Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. Funding Information: We are very grateful to all patients who contributed samples and participated in the study. We thank all the staff of the Day Treatment Unit, Oxford Cancer Centre and the Brodey Centre at the Horton General Hospital. We are grateful to all the staff of the Oxford University Hospitals NHS Foundation Trust haematology and biochemistry laboratory and thank T. James for his facilitation, as well as the staff of the Oxford Radcliffe Biobank and Churchill Hospital Sample Handling Lab. This study was funded by a Wellcome Intermediate Clinical Fellowship to B.P.F. (no. 201488/Z/16/Z), additionally supporting A.V.A. and I.N. R.A.W. is funded by a Wellcome Trust Doctoral Training Fellowship (no. BST00070). O.T. is supported by the Clarendon Fund, St. Edmund Hall and an Oxford Australia Scholarship. W.Y. is an NIHR academic clinical fellow and is supported by a CRUK predoctoral fellowship (reference RCCTI\100019). R.C. was supported by a CRUK Clinical Research Training Fellowship (S_3578). C.A.T. was funded by the Engineering & Physical Sciences Research Council and the Balliol Jowett Society (no. D4T00070). D.C. is funded by a Cancer Research UK Advanced Clinician Scientist Fellowship (C26642/A27963). J.J.G. is supported by an NIHR Clinical Lectureship. M.R.M. and B.P.F. are supported by the NIHR Oxford Biomedical Research Centre. K.M. and P.E. are supported by the NIHR Leeds Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. Publisher Copyright: © 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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 IL7. We found that rs16906115 forms a B cell-specific expression quantitative trait locus (eQTL) to IL7 in patients. Patients carrying the risk allele demonstrate increased pre-treatment B cell IL7 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+ 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.
AB - 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 IL7. We found that rs16906115 forms a B cell-specific expression quantitative trait locus (eQTL) to IL7 in patients. Patients carrying the risk allele demonstrate increased pre-treatment B cell IL7 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+ 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.
UR - http://www.scopus.com/inward/record.url?scp=85144103834&partnerID=8YFLogxK
U2 - 10.1038/s41591-022-02095-5
DO - 10.1038/s41591-022-02095-5
M3 - Article
C2 - 36526722
AN - SCOPUS:85144103834
SN - 1078-8956
VL - 28
SP - 2592
EP - 2600
JO - Nature Medicine
JF - Nature Medicine
IS - 12
ER -