Abstract 4655: The prognostic significance of a 12-chemokine tertiary lymphoid structure (TLS) gene signature in uveal melanoma (UM)
Authors: Abushukair Hassan Mohammed , Al-Bzour Ayah , Knight Andrew , Storkus Walter J. , Kirkwood John M. , Karapetyan Lilit 
Published: April 2023

Introduction Lymphoid aggregates are commonly associated with better prognosis and enhanced response to immune modulators in several cancers. Considering the immune-privileged status of the eye we sought to investigate the immune, genomic and prognostic significance of 12-chemokine TLS gene signature in UM patients.

Methods A previously validated 12-chemokine gene signature established in cutaneous melanoma was used (CCL2-5, CCL8, CCL18, CCL19, CCL21, CXCL9-11, CXCL13). Clinical, genomic and transcriptomic data was retrieved from The Cancer Genomic Atlas UM cohort (n = 80) and the GSE22138 dataset (n = 63) from the gene expression omnibus. The signature was constructed using principal component (PC) analyses based on the first PC1. Patients with a PC1 score &gt; +4 or &lt; -4 were considered gene expression profile (GEP) high and low, respectively. The CIBERSORT algorithm was used to estimate the immune composition in tumor tissue. Gene Set Enrichment Analysis (GSEA) was conducted using the Hallmarks gene sets. A cytotoxic T cell (CTL) score was calculated based on the coordinate expression of CD8A, CD8B, GZMA, GZMB and PRF1.

Results The 12-chemokine score was higher among epithelioid vs. spindle cell or mixed histology (mean: 7.84 vs -4.91 vs 1.22, p = 0.038) and there were no differences across different tumor sites or stages. GEP low patients had significantly better overall survival (HR: 0.10, 95% CI: 0.03-0.36, p &lt; 0.001) and disease-free survival (HR: 0.23, 95% CI: 0.06-0.88, p = 0.031) compared to GEP high. Metastasis-free survival was not significantly different in the second cohort (0.47, 95% CI: 0.16-1.42, p = 0.182). The EIF1AX and SF3B1 driver mutations were significantly more frequent among GEP low (22.5% and 35%) compared to GEP high patients (3.7% and 7.4%). Tumor mutational burden and other driver mutations (BAP1, GNA11, GNAQ) were similar between both groups. GSEA revealed significant enrichment of inflammatory response (IFN-α/γ, TNF-α signalling via NF-κB, IL2-STAT5, IL6-JAK-STAT3 signalling), Epithelial Mesenchymal Transition (EMT), reactive oxygen species, and angiogenesis pathways in GEP high patients. GEP low patients had lower CTL scores compared to GEP high patients (31.3 vs 11.4, p &lt; 0.001). M1 macrophages, CD8+ and regulatory T cells were enriched in GEP high patients whereas CD4+ memory T cells and activated dendritic cells were more prevalent in GEP low patients.

Conclusion Uveal melanoma patients with a high GEP score had inferior survival and were enriched for inflammatory, angiogenic, and EMT pathways, while patients with a low GEP score were more likely to express prognostically favourable driver mutations (EIF1AX, SF3B1). Our results suggest a variable prognostic role of lymphoid aggregates in the setting of UM compared to other solid tumors, warranting further investigation for their differential underlying mechanisms.

Citation Format: Hassan Mohammed Abushukair, Ayah Al-Bzour, Andrew Knight, Walter J. Storkus, John M. Kirkwood, Lilit Karapetyan. The prognostic significance of a 12-chemokine tertiary lymphoid structure (TLS) gene signature in uveal melanoma (UM). [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 4655.