Abstract 2144: Proteomic study reveals predictive biomarkers of immune-related adverse events in melanoma
Authors: Wilmot Muhammad Zaki Fadlullah , Kovacsovics Magdalena , Wang Xuechen , Coleman Samuel , Marsiglio John , Gibson Berit , DeRose Yoko , Zhou Qin , Larson Annaleah , Hyngstrom John , Haaland Ben , Hu-Lieskovan Siwen , Tan Aik Choon 
Published: April 2023

Advances in immunotherapy including immune checkpoint inhibitors (ICIs) have transformed the standard of care of many cancers including melanoma. However, the benefit of ICIs is hampered by immune related adverse events (irAEs). The frequency of irAEs varies between ICI treatments and cancer types. These irAEs represent autoimmune reactions that can affect diverse organs, with distinct biology, onset, and severity from their de novo autoimmune disease counterparts. Some irAEs could persist and develop into chronic comorbidities, and a subset of severe irAEs could led to death. Yet, little is known about the underlying molecular mechanisms and no biomarkers are currently available to predict irAEs after ICI treatment.

We aimed to identify soluble predictive biomarkers of irAE by non-invasive means using high-throughput Olink Proteomics assay. We collected plasma from 31 melanoma patients before ICI treatment. 25 patients developed severe irAE (grade 3 or above) at one or more organ system including hepatobiliary (n=9), endocrine (n=8), gastrointestinal (n=6), skin and subcutaneous tissue (n=6), musculoskeletal and connective tissue (n=5), blood and lymphatic (n=4) and respiratory (n=1) after receiving ICI, whereas 6 patients have no severe irAEs. The relative expression of 1,472 probes corresponding to 1,463 proteins as part of the Olink Cardiometabolic, Neurology, Inflammation and Oncology panels were quantified as Normalized Protein eXpresion (NPX) on a log-2 scale. Two-tailed T-test was performed in comparing the severe irAEs vs no irAE groups to determine the difference proteins and p &lt; 0.05 and FDR &lt; 0.1 was deemed to be significant. Similarly, we performed organ-specific irAEs using the same approach. Proteins were assessed by enrichment analysis using EnrichR.

Exploratory analysis revealed elevated expression of CD4 and CD8 cell markers such as IL7R, S100A4, GZMA and GZMB in patients that developed severe irAEs. More broadly, pathway enrichment analysis suggest chemokines and cytokine receptor related pathways were enriched in these patients implicating the role of immune system and inflammatory mediators as potential biomarkers of irAE. In particular, the expression of some interleukin family members appears to be a good predictor of irAE toxicity. Interestingly, our analysis revealed irAE at various organ tissues were associated with different set of proteins suggesting an organ specific protein signature.

In conclusion, we demonstrated the potential utility of soluble protein in the peripheral blood measurement at baseline prior to ICI treatment for prediction of irAE risk. This finding will be evaluated in a larger independent cohort.

Citation Format: Muhammad Zaki Fadlullah Wilmot, Magdalena Kovacsovics, Xuechen Wang, Samuel Coleman, John Marsiglio, Berit Gibson, Yoko DeRose, Qin Zhou, Annaleah Larson, John Hyngstrom, Ben Haaland, Siwen Hu-Lieskovan, Aik Choon Tan. Proteomic study reveals predictive biomarkers of immune-related adverse events in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2144.