Germline Immunomodulatory Expression Quantitative Trait Loci (ieQTLs) Associated with Immune-Related Toxicity from Checkpoint Inhibition

Robert Ferguson^1,2,3*, Vylyny Chat^1,2,3*, Leah Morales^1,2,3, Danny Simpson^1,2,3, Kelsey Monson^1,2,3, Elisheva Cohen^1,2,3,Sarah Zusin^1,2,3, Gabriele Madonna⁴, Mariaelena Capone⁴, Ester Simeone⁴, Anna Pavlick⁵, Jason Luke^6,7, Thomas F Gajewski^8,9,10, Iman Osman^1,3,11,12, Paolo Antonio Ascierto⁴, Jeffrey Weber^1,3,11, Tomas Kirchhoff^1,2,3 1Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA<br> 2Departments of Population Health and Environmental Medicine, New York University- Grossman School of Medicine, New York, NY, USA<br> 3The Interdisciplinary Melanoma Cooperative Group, New York University-Grossman School of Medicine, New York, NY, USA<br> 4Melanoma Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy<br> 5Division of Hematology &amp; Medical Oncology, the Cutaneous Oncology Program, Weill Cornell Medicine and New York-Presbyterian, New York, USA<br> 6Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA.<br> 7UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA.<br> 8Department of Pathology, University of Chicago, Chicago, IL, USA. 9Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA.<br> 10Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA.<br> 11Department of Medicine, New York University-Grossman School of Medicine, New York, NY, USA<br> 12Ronald O. Perelman Department of Dermatology, New York University-Grossman School of Medicine, New York, NY, USA *These authors contributed equally to the work Corresponding author: Tomas Kirchhoff, PhD <strong>ABSTRACT</strong><br> <strong>Background:</strong> Immune-checkpoint inhibition (ICI) has improved clinical outcomes for metastatic melanoma patients, however, 65-80% of patients treated with ICI experience immune-related adverse events (irAEs). Given the plausible link of irAEs with underlying host immunity, we explored if germline genetic variants controlling the expression of 42 immunomodulatory genes<br> were associated with the risk of irAEs in melanoma patients treated with the single-agent anti- CTLA-4 antibody ipilimumab (IPI).<br> <strong>Methods:</strong> We identified 42 immunomodulatory expression quantitative trait loci (ieQTLs) most significantly associated with the expression of 382 immune-related genes. These germline variants were genotyped in IPI-treated melanoma patients, collected as part of a multiinstitutional collaboration. We tested the association of ieQTLs with irAEs in a discovery cohort of 95 patients followed by validation in an additional 97 patients.<br> Results: We found that the alternate allele of rs7036417, a variant linked to increased expression of SYK, was strongly associated with an increased risk of grade 3-4 toxicity (OR= 7.46; 95% CI=2.65-21.03; p=1.43E-04). This variant was not associated with response (OR= 0.90; 95% CI=0.37-2.21; p=0.82).<br> Conclusion: We report that rs7036417 associates with increased risk of severe irAEs, independent of IPI efficacy. SYK plays an important role in B-cell/T-cell expansion and increased pSYK has been reported in patients with autoimmune disease. The association between rs7036417 and IPI irAEs in our data suggests a role of SYK over-expression in irAE development. These findings support the hypothesis that inherited variation in immune-related pathways modulate ICI toxicity and suggest SYK as a possible future target for therapies to reduce irAEs. <strong>Keywords:</strong> irAEs; germline variants; immune checkpoint inhibition; melanoma <strong>Funding:</strong> This research was funded by the Italian Ministry of Health (IT-MOH) through “Ricerca Corrente”, grants number M2/2 and L2-1.