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

Robert Ferguson1,2,3*, Vylyny Chat1,2,3*, Leah Morales1,2,3, Danny Simpson1,2,3, Kelsey Monson1,2,3, Elisheva Cohen1,2,3,Sarah Zusin1,2,3, Gabriele Madonna4, Mariaelena Capone4, Ester Simeone4, Anna Pavlick5, Jason Luke6,7, Thomas F Gajewski8,9,10, Iman Osman1,3,11,12, Paolo Antonio Ascierto4, Jeffrey Weber1,3,11, Tomas Kirchhoff1,2,3

1Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA
2Departments of Population Health and Environmental Medicine, New York University- Grossman School of Medicine, New York, NY, USA
3The Interdisciplinary Melanoma Cooperative Group, New York University-Grossman School of Medicine, New York, NY, USA
4Melanoma Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy
5Division of Hematology & Medical Oncology, the Cutaneous Oncology Program, Weill Cornell Medicine and New York-Presbyterian, New York, USA
6Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
7UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA.
8Department of Pathology, University of Chicago, Chicago, IL, USA.

9Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA.
10Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA.
11Department of Medicine, New York University-Grossman School of Medicine, New York, NY, USA
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

ABSTRACT
Background: 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
were associated with the risk of irAEs in melanoma patients treated with the single-agent anti- CTLA-4 antibody ipilimumab (IPI).
Methods: 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.
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).
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.

Keywords: irAEs; germline variants; immune checkpoint inhibition; melanoma

Funding: This research was funded by the Italian Ministry of Health (IT-MOH) through “Ricerca Corrente”, grants number M2/2 and L2-1.