Abstract 1404: Blood-based transcriptomics provides novel insights into Sjögren's syndrome-associated lymphomagenesis

Abstract Sjögren's syndrome (SS) is a debilitating autoimmune disorder that carries the highest risk of progressing to lymphoma among all autoimmune diseases, with up to 10% of patients developing SS-associated lymphoma. However, the underlying mechanisms are unknown, and there are currently no actionable targets for prevention and therapeutic intervention. To elucidate the mechanisms associated with SS-lymphoma, we performed RNA-Seq in peripheral blood from SS patients without (n=11) or with lymphoma (n=8). Differential gene expression and pathway analysis identified TNF-α signaling via NF-κB, inflammatory response and interferon gamma (IFN-γ) response as the top pathways enriched in SS-lymphoma patients. Interestingly, the enriched IFN-γ response pathway is consistent with our published work identifying elevated IFN-γ transcript levels in salivary gland tissues from SS patients with lymphoma. Central to SS pathogenesis is the elevation of TNF-α signaling, triggering NF-κB pathway activation and subsequent inflammation, along with inflammasome activation, in line with prior observations. Our data reveal significant upregulation of these pathways in SS-lymphoma patients, which together with the inflammatory response and IFN-γ pathway enrichment, support the idea that persistent autoimmune-related chronic inflammation fosters a microenvironment conducive to lymphomagenesis. Next, we sought to assess the impact of SS immune landscape in SS-lymphoma by performing an immune modular analysis using an established framework of 97 whole blood transcriptomics modules (Pascual), derived from transcripts co-expressed in blood across various autoimmune conditions. This analysis revealed a significant downregulation of T-cell and enrichment of B-cell modules in SS-lymphoma compared to SS patients. These findings are consistent with our biopsy results, showing lower T cell counts in high-grade vs. low-grade SS patients. As patients with high-grade SS are more likely to develop SS-lymphoma, these data possibly suggest that suppressed T-cell responses are involved in lymphomagenesis. In addition, the significant enrichment in B-cell transcriptional modules mirrors the observed clinical increase in B cell counts during the transition to SS-lymphoma. Germline mutations in B-cells are thought to drive the clonal expansion of malignant B cells, which may contribute to the observed increase of B cell transcriptomes in SS patients developing lymphoma. We are currently investigating the gene mutation landscape in these datasets to better understand their contribution to SS- lymphomagenesis. This study provides preliminary evidence that chronic inflammation along with dysregulation of T and B compartments in SS significantly contributes to lymphoma progression, emphasizing the need for further research to uncover the molecular basis and develop early diagnostic/intervention tools. Citation Format: Ada Gjyrezi, Charalampos Skarlis, Paul Zumbo, Doron Betel, Ioanna E. Stergiou, Michael Voulgarelis, Clio P. Mavragani, Paraskevi Giannakakou. Blood-based transcriptomics provides novel insights into Sjögren's syndrome-associated lymphomagenesis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 1404.