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Genetic determinants of immune-related adverse events in patients with melanoma receiving immune checkpoint inhibitors

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Abstract

Background

Immune checkpoint inhibitors (ICIs) can cause profound immune-related adverse events (irAEs). The host genetic background is likely to play a role in irAE susceptibility because the presentation of toxicity varies among patients and many do not develop irAEs despite continued ICI use. We sought to identify potential genetic markers conferring risk for irAEs.

Methods

We conducted a pilot exploratory study in 89 melanoma patients who received ICIs (44 with irAEs, and 45 without irAEs after at least 1 year from starting treatment). Genotyping was performed using the Infinium Multi-Ethnic Global-8 v1.0 Bead Chip. The genotype data were extracted using PLINK (v1.90b3.34) and processed for quality control. Population structure-based clustering was carried out using IBS matrix, pairwise population concordance test (p < 1 × 10–3), and phenotype distribution for all study participants, resulting in seven population structure-based clusters. In the analytical stage, 599,931 variants in autosomal chromosomes were included for the association study. The association test was performed using an additive genetic model with exact logistic regression, adjusted for age, sex, and population cluster.

Results

A total of 30 variants or single-nucleotide polymorphisms with p < 1 × 10–4 were identified; 12 were associated with an increased risk of irAEs, and the remaining 18 were associated with a decreased risk. Overall, nine of the identified single-nucleotide polymorphisms mapped to eight unique genes that have been associated with autoimmunity or inflammatory diseases.

Conclusion

Several genetic variants associated with irAEs were identified. Additional larger studies are needed to validate these findings and establish their potential functional relevance.

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Abbreviations

CI:

Confidence interval

CTLA-4:

Cytotoxic T-cell lymphocyte-associated protein-4

ICI:

Immune checkpoint inhibitor

irAE:

Immune-related adverse event

OR:

Odds ratio

PD-1/PD-L1:

Programmed cell death-1/programmed cell death-ligand 1

SNP:

Single-nucleotide polymorphism

References

  1. KEYTRUDA- Pembrolizumab [package insert]. County Cork IM, 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125514s067lbl.pdf. Accessed 1 May 2020

  2. YERVOY-ipilimumab [package insert]. Princeton NBS, 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125377s104lbl.pdf. Accessed 1 May 2020

  3. Opdivo-nivolumab [package insert]. Princeton NBMS, 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125554s075lbl.pdf. Accessed 1 May 2020

  4. Abdel-Wahab N, Shah M, Suarez-Almazor ME (2016) Adverse events associated with immune checkpoint blockade in patients with cancer: a systematic review of case reports. PLoS ONE 11(7):e0160221

    Article  PubMed  PubMed Central  Google Scholar 

  5. Bertrand A, Kostine M, Barnetche T, Truchetet ME, Schaeverbeke T (2015) Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis. BMC Med 13:211

    Article  PubMed  PubMed Central  Google Scholar 

  6. Wang Y, Zhou S, Yang F, Qi X, Wang X, Guan X et al (2019) Treatment-related adverse events of PD-1 and PD-L1 inhibitors in clinical trials: a systematic review and meta-analysis. JAMA Oncol 5(7):1008–1019

    Article  PubMed  PubMed Central  Google Scholar 

  7. Le Burel S, Champiat S, Routier E, Aspeslagh S, Albiges L, Szwebel TA et al (2018) Onset of connective tissue disease following anti-PD1/PD-L1 cancer immunotherapy. Ann Rheum Dis 77(3):468–470

    Article  PubMed  Google Scholar 

  8. Thompson JA, Schneider BJ, Brahmer J, Andrews S, Armand P, Bhatia S et al (2019) Management of immunotherapy-related toxicities, version 1.2019. J Natl Compr Cancer Netw 17(3):255–289

    Article  CAS  Google Scholar 

  9. Balint B, Bhatia KP (2016) Stiff person syndrome and other immune-mediated movement disorders—new insights. Curr Opin Neurol 29(4):496–506

    Article  CAS  PubMed  Google Scholar 

  10. Muller R, Heber B, Hashimoto T, Messer G, Mullegger R, Niedermeier A et al (2009) Autoantibodies against desmocollins in European patients with pemphigus. Clin Exp Dermatol 34(8):898–903

    Article  CAS  PubMed  Google Scholar 

  11. Du Y, Wu X, Chen M, Wang W, Xv W, Ye L et al (2017) Elevated semaphorin5A in systemic lupus erythematosus is in association with disease activity and lupus nephritis. Clin Exp Immunol 188(2):234–242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lyu M, Li Y, Hao Y, Sun T, Liu W, Lyu C et al (2015) Elevated semaphorin 5A correlated with Th1 polarization in patients with chronic immune thrombocytopenia. Thromb Res 136(5):859–864

    Article  CAS  PubMed  Google Scholar 

  13. Gras C, Eiz-Vesper B, Jaimes Y, Immenschuh S, Jacobs R, Witte T et al (2014) Secreted semaphorin 5A activates immune effector cells and is a biomarker for rheumatoid arthritis. Arthritis Rheumatol 66(6):1461–1471

    Article  CAS  PubMed  Google Scholar 

  14. Labiad Y, Venton G, Farnault L, Baier C, Colle J, Mercier C et al (2018) A transcriptomic signature predicting septic outcome in patients undergoing autologous stem cell transplantation. Exp Hematol 65:49–56

    Article  CAS  PubMed  Google Scholar 

  15. Martinez-Hernandez R, Serrano-Somavilla A, Ramos-Levi A, Sampedro-Nunez M, Lens-Pardo A, Munoz De Nova JL et al (2019) Integrated miRNA and mRNA expression profiling identifies novel targets and pathological mechanisms in autoimmune thyroid diseases. EBioMedicine 50:329–342

    Article  PubMed  PubMed Central  Google Scholar 

  16. Glawe JD, Mijalis EM, Davis WC, Barlow SC, Gungor N, McVie R et al (2013) SDF-1-CXCR4 differentially regulates autoimmune diabetogenic T cell adhesion through ROBO1-SLIT2 interactions in mice. Diabetologia 56(10):2222–2230

    Article  CAS  PubMed  Google Scholar 

  17. Aslam MM, John P, Fan KH, Bhatti A, Jahangir S, Feingold E et al (2019) Exploration of shared genetic susceptibility loci between type 1 diabetes and rheumatoid arthritis in the Pakistani population. BMC Res Notes 12(1):544

    Article  PubMed  PubMed Central  Google Scholar 

  18. Inshaw JRJ, Cutler AJ, Crouch DJM, Wicker LS, Todd JA (2020) Genetic variants predisposing most strongly to type 1 diabetes diagnosed under age 7 years lie near candidate genes that function in the immune system and in pancreatic beta-cells. Diabetes Care 43(1):169–177

    Article  CAS  PubMed  Google Scholar 

  19. Bins S, Basak EA, El Bouazzaoui S, Koolen SLW, Oomen-de Hoop E, van der Leest CH et al (2018) Association between single-nucleotide polymorphisms and adverse events in nivolumab-treated non-small cell lung cancer patients. Br J Cancer 118(10):1296–1301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Cappelli LC, Dorak MT, Bettinotti MP, Bingham CO, Shah AA (2019) Association of HLA-DRB1 shared epitope alleles and immune checkpoint inhibitor-induced inflammatory arthritis. Rheumatology 58(3):476–480

    Article  CAS  PubMed  Google Scholar 

  21. Khan Z, Hammer C, Guardino E, Chandler GS, Albert ML (2019) Mechanisms of immune-related adverse events associated with immune checkpoint blockade: using germline genetics to develop a personalized approach. Genome Med 11(1):39

    Article  PubMed  PubMed Central  Google Scholar 

  22. Chat V, Ferguson R, Simpson D, Kazlow E, Lax R, Moran U et al (2019) Autoimmune genetic risk variants as germline biomarkers of response to melanoma immune-checkpoint inhibition. Cancer Immunol Immunother 68(6):897–905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Dulos J, Carven GJ, van Boxtel SJ, Evers S, Driessen-Engels LJ, Hobo W et al (2012) PD-1 blockade augments Th1 and Th17 and suppresses Th2 responses in peripheral blood from patients with prostate and advanced melanoma cancer. J Immunother 35(2):169–178

    Article  CAS  PubMed  Google Scholar 

  24. von Euw E, Chodon T, Attar N, Jalil J, Koya RC, Comin-Anduix B et al (2009) CTLA4 blockade increases Th17 cells in patients with metastatic melanoma. J Transl Med 7:35

    Article  Google Scholar 

  25. Bailey SR, Nelson MH, Himes RA, Li Z, Mehrotra S, Paulos CM (2014) Th17 cells in cancer: the ultimate identity crisis. Front Immunol 5:276

    Article  PubMed  PubMed Central  Google Scholar 

  26. Gutierrez-Arcelus M, Rich SS, Raychaudhuri S (2016) Autoimmune diseases—connecting risk alleles with molecular traits of the immune system. Nat Rev Genet 17(3):160–174

    Article  PubMed  PubMed Central  Google Scholar 

  27. Okazaki T, Honjo T (2006) The PD-1-PD-L pathway in immunological tolerance. Trends Immunol 27(4):195–201

    Article  CAS  PubMed  Google Scholar 

  28. Scalapino KJ, Daikh DI (2008) CTLA-4: a key regulatory point in the control of autoimmune disease. Immunol Rev 223:143–155

    Article  CAS  PubMed  Google Scholar 

  29. Schildberg FA, Klein SR, Freeman GJ, Sharpe AH (2016) Coinhibitory pathways in the B7-CD28 ligand-receptor family. Immunity 44(5):955–972

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP et al (1995) Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270(5238):985–988

    Article  CAS  Google Scholar 

  31. Barreto M, Santos E, Ferreira R, Fesel C, Fontes MF, Pereira C et al (2004) Evidence for CTLA4 as a susceptibility gene for systemic lupus erythematosus. Eur J Hum Genetics 12(8):620–626

    Article  CAS  Google Scholar 

  32. Lee YH, Bae SC, Kim JH, Song GG (2015) Meta-analysis of genetic polymorphisms in programmed cell death 1. Associations with rheumatoid arthritis, ankylosing spondylitis, and type 1 diabetes susceptibility. Z Rheumatol 74(3):230–239

    Article  CAS  PubMed  Google Scholar 

  33. Lee YH, Kim JH, Seo YH, Choi SJ, Ji JD, Song GG (2014) CTLA-4 polymorphisms and susceptibility to inflammatory bowel disease: a meta-analysis. Hum Immunol 75(5):414–421

    Article  CAS  PubMed  Google Scholar 

  34. Lee YH, Woo JH, Choi SJ, Ji JD, Song GG (2009) Association of programmed cell death 1 polymorphisms and systemic lupus erythematosus: a meta-analysis. Lupus 18(1):9–15

    Article  CAS  PubMed  Google Scholar 

  35. Li G, Shi F, Liu J, Li Y (2014) The effect of CTLA-4 A49G polymorphism on rheumatoid arthritis risk: a meta-analysis. Diagn Pathol 9:157

    Article  PubMed  PubMed Central  Google Scholar 

  36. Liu JL, Zhang FY, Liang YH, Xiao FL, Zhang SQ, Cheng YL et al (2009) Association between the PD1.3A/G polymorphism of the PDCD1 gene and systemic lupus erythematosus in European populations: a meta-analysis. J Eur Acad Dermatol Venereol 23(4):425–432

    Article  PubMed  Google Scholar 

  37. Wu J, Zhang L, Zhou Y (2016) The association between CTLA-4 (+49 A/G) polymorphism and susceptibility to ankylosing spondylitis: a meta-analysis. Int J Rheum Dis 19(12):1237–1243

    Article  CAS  PubMed  Google Scholar 

  38. Queirolo P, Dozin B, Morabito A, Banelli B, Carosio R, Fontana V et al (2018) CTLA-4 gene variant − 1661A>G may predict the onset of endocrine adverse events in metastatic melanoma patients treated with ipilimumab. Eur J Cancer 97:59–61

    Article  CAS  PubMed  Google Scholar 

  39. Kostine M, Rouxel L, Barnetche T, Veillon R, Martin F, Dutriaux C et al (2018) Rheumatic disorders associated with immune checkpoint inhibitors in patients with cancer-clinical aspects and relationship with tumour response: a single-centre prospective cohort study. Ann Rheum Dis 77(3):393–398

    Article  CAS  PubMed  Google Scholar 

  40. Magis Q, Gaudy-Marqueste C, Basire A, Loundou A, Malissen N, Troin L et al (2018) Diabetes and blood glucose disorders under Anti-PD1. J Immunother 41(5):232–240

    Article  CAS  PubMed  Google Scholar 

  41. Brownlie RJ, Zamoyska R, Salmond RJ (2018) Regulation of autoimmune and anti-tumour T-cell responses by PTPN22. Immunology 154(3):377–382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Judd J, Zibelman M, Handorf E, O’Neill J, Ramamurthy C, Bentota S et al (2017) Immune-related adverse events as a biomarker in non-melanoma patients treated with programmed cell death 1 inhibitors. Oncologist 22(10):1232–1237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Downey SG, Klapper JA, Smith FO, Yang JC, Sherry RM, Royal RE et al (2007) Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res 13(22 Pt 1):6681–6688

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Haratani K, Hayashi H, Chiba Y, Kudo K, Yonesaka K, Kato R et al (2018) Association of immune-related adverse events with Nivolumab efficacy in non-small-cell lung cancer. JAMA Oncol 4(3):374–378

    Article  PubMed  Google Scholar 

  45. Chowell D, Morris LGT, Grigg CM, Weber JK, Samstein RM, Makarov V et al (2018) Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy. Science 359(6375):582–587

    Article  CAS  PubMed  Google Scholar 

  46. Liu QF, Li Y, Zhao QH, Wang ZY, Hu S, Yang CQ et al (2015) Association of STAT4 rs7574865 polymorphism with susceptibility to inflammatory bowel disease: a systematic review and meta-analysis. Clin Res Hepatol Gastroenterol 39(5):627–636

    Article  CAS  PubMed  Google Scholar 

  47. Ng SC, Tsoi KK, Kamm MA, Xia B, Wu J, Chan FK et al (2012) Genetics of inflammatory bowel disease in Asia: systematic review and meta-analysis. Inflamm Bowel Dis 18(6):1164–1176

    Article  PubMed  Google Scholar 

  48. Siakavellas SI, Bamias G (2018) Checkpoint inhibitor colitis: a new model of inflammatory bowel disease? Curr Opin Gastroenterol 34(6):377–383

    Article  CAS  PubMed  Google Scholar 

  49. Dougan M (2017) Checkpoint blockade toxicity and immune homeostasis in the gastrointestinal tract. Front Immunol 8:1547

    Article  PubMed  PubMed Central  Google Scholar 

  50. Geukes Foppen MH, Rozeman EA, van Wilpe S, Postma C, Snaebjornsson P, van Thienen JV et al (2018) Immune checkpoint inhibition-related colitis: symptoms, endoscopic features, histology and response to management. ESMO Open 3(1):e000278

    Article  PubMed  PubMed Central  Google Scholar 

  51. Wang Y, Abu-Sbeih H, Mao E, Ali N, Qiao W, Trinh VA et al (2018) Endoscopic and histologic features of immune checkpoint inhibitor-related colitis. Inflamm Bowel Dis 24(8):1695–1705

    Article  PubMed  Google Scholar 

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Acknowledgements

We are grateful to Erica Goodoff, from the Department of Scientific Publications, Research Medical Library at The University of Texas MD Anderson Cancer Center for her valuable contribution. We are also grateful to Haidee Chancoco, from the Biospecimen Extraction Resource of MD Anderson Cancer Center for samples processing and DNA extraction.

Funding

This study was funded by a Thrive grant from the Health and Environmental Science Institute to perform this study (Grant Thrive FP00000078). The funding agency had no role in the study’s design; collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit this paper for publication. The University of Texas MD Anderson Cancer Center is supported in part by the National Institutes of Health through Cancer Center Support Grant P30CA016672 and CA016672 (ATGC).

Author information

Author notes

  1. Sanjay S. Shete and Maria E. Suarez-Almazor contributed equally to this work.

Authors and Affiliations

  1. Section of Rheumatology and Clinical Immunology, Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Noha Abdel-Wahab, Jean H. Tayar & Maria E. Suarez-Almazor

  2. Department of Rheumatology and Rehabilitation, Faculty of Medicine, Assiut University Hospitals, Assiut, Egypt

    Noha Abdel-Wahab

  3. Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Noha Abdel-Wahab & Adi Diab

  4. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Robert K. Yu & Sanjay S. Shete

  5. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Andrew Futreal

  6. Russell/Engleman Rheumatology Research Center, Department of Medicine, University of California San Francisco, San Francisco, CA, USA

    Lindsey A. Criswell

  7. Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Ramona Dadu

  8. Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Vickie Shannon

  9. Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Sanjay S. Shete

  10. Department of Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Maria E. Suarez-Almazor

Authors
  1. Noha Abdel-Wahab
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Contributions

MES-A and SSS had full access to all of the data in the study and take responsibility for the integrity and the accuracy of the data analysis. Study concept and design: NA, SSS, MES-A. Acquisition of data: NA, AD. Analysis and interpretation of data: NA, RKY. Quality assessment: RKY. Drafting of the manuscript: NA. Critical revision of the manuscript for important intellectual content: AD, RKY, AF, LAC, JHT, RD, VS, SSS, MES-A. Statistical analysis: NA, RKY. Administrative, technical, or material support: SSS, MES-A. Study supervision: SSS, MES-A. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Sanjay S. Shete or Maria E. Suarez-Almazor.

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Ethics approval and consent to participate

The study was approved by the Institutional Review Board at The University of Texas MD Anderson Cancer Center. IRB number: PA16-0928. All patients signed an informed consent prior to study participation.

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The is the first pilot genome-wide study to identify genetic variants that may be associated with the risk of developing immune-related adverse events in melanoma patients treated with checkpoint inhibitors.

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Abdel-Wahab, N., Diab, A., Yu, R.K. et al. Genetic determinants of immune-related adverse events in patients with melanoma receiving immune checkpoint inhibitors. Cancer Immunol Immunother 70, 1939–1949 (2021). https://doi.org/10.1007/s00262-020-02797-0

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