Differential Expression of Aminoacyl-tRNA Synthetases Predicts Treatment Outcomes and Immune Microenvironment Composition in Melanoma Patients

Preethi Kumaran

Mentor: Dr. Naoko Takebe and Dr. Vishnu Nagalapuram, University of Oklahoma Stephenson Cancer Center.

Date/Time: August 22nd, 2025 at 10:15 AM.

Abstract: Melanoma is the malignancy of melanin-producing cells in the basal layer of the epidermis. Though it accounts for only 1% of skin cancers, it is responsible for over 80% of skin cancer-related deaths1. Advances in targeted therapies and immune checkpoint inhibitors have significantly improved patient outcomes, however, there is no standardized threshold to predict clinical outcomes for patients undergoing treatment. One major source of resistance to ICI therapy is the presence of tumor-associated macrophages (TAMs), particularly the M2-like subtype, which suppress CD8+ T cell function and creates an immunosuppressive tumor microenvironment 3.

tRNAs play a critical role in epigenetically regulating gene expression in cancer cells, and aminoacyl-tRNA synthetases (ARSs) ligate amino acids to their corresponding tRNAs 2. VARS has been identified as a key regulator of the immunosuppressive tumor microenvironment in melanoma, with expression positively correlated with M2-like TAM infiltration and negatively correlated with CD8+ T cell infiltration 3. Additionally, VARS is upregulated in MAPK-targeted therapy-resistant melanoma and contributes to codon-biased translational reprogramming 4. Similarly, WARS has been implicated in immune regulation and inflammatory responses, influencing immune cell signaling and the tumor microenvironment. QARS may have functions related to cellular stress responses and immune modulation.

The objective of this study was to evaluate the association between these three ARS gene expressions and clinical outcomes, as well as treatment responses in melanoma patients. We utilized RNA-seq data and clinical data from over 500 melanoma patients provided by the ORIEN Avatar database. Patients were categorized into curative context (84 patients) and advanced context (230 patients) groups, with treatment cohorts including immunotherapy, targeted therapy, BRAF inhibitors, and MEK inhibitors. High ARS expression was expected to correlate with adverse clinical outcomes and poor treatment responses to ICIs and BRAF/MEK inhibitors.

Analysis showed that lower WARS expression was significantly associated with improved recurrence-free survival in the curative surgery group (HR: 0.446, p=0.049), while higher WARS expression was significantly associated with worse progression-free survival in immunotherapy patients (first-line HR: 3.550, p=0.0048; any-line HR: 2.284, p=0.0032). Higher QARS expression consistently predicted poor outcomes across multiple treatments, with worse PFS in any-line immunotherapy (HR: 1.943, p=0.0091), targeted therapy (HR: 2.883, p=0.0336), BRAF inhibitors (HR: 3.442, p=0.0175), and MEK inhibitors (HR: 2.893, p=0.0404).

Additionally, patients with tumor microenvironment data were analyzed to assess differences in immune cell infiltration between high versus low ARS expression groups. WARS expression showed correlation with pro-inflammatory immune responses including increased M1 macrophages (4.48-fold, p<0.0001), activated NK cells (4.48-fold, p=0.0011), and CD8+ T cells (3.48-fold, p=0.004). QARS was associated with adaptive immunity markers including naive B cells (14.50-fold, p<0.001) and reduced M2 macrophages (0.34-fold, p=0.007). VARS did not show any significant immune association as previously predicted. These findings suggest that specific ARSs, like WARS and QARS, should be further studied as prognostic markers and as potential therapeutic targets in immunotherapy-resistant melanoma.