POS0371 ASSOCIATION OF IgG4-RELATED DISEASE WITH AN IMMUNOLOGIC RESPONSE TO CANCER

Background: Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated fibro-inflammatory disease of unclear etiology. Oligoclonal expansion of plasmablasts and effector memory T cells in blood and tissues of IgG4-RD patients suggests an immune response triggered by still unknown antigen(s). In some patients IgG4-RD is diagnosed in close temporal proximity to a solid or hematologic malignancy raising the possibility that tumor antigens might elicit a paraneoplastic form of IgG4-RD [1]. The relationship between IgG4-RD and cancer remains unclear and the potential mechanisms tying these two conditions have not been determined to date. Objectives: In the present work we aimed to gain clues about a possible mechanistic link between IgG4-RD and cancer by comparing the T-cell receptor (TCR) beta chain repertoire of tissue infiltrating T cells from four patients diagnosed with IgG4-RD and cancer in close temporal proximity. Methods: IgG4-RD patients with a history of cancer and available tissues from both IgG4-RD and tumor affected organs were included in this study. Patients should also have a third tissue biopsy avaible from organs affected by other inflammatory conditions (e.g. diverticulitis, polips, or cholecystitis) to be used as internal control. Genomic DNA was extracted from FFPE tissues of organs affected by IgG4-RD, cancer, and control tissue of the same patient. High-throughput sequencing of the beta chain of the TCR of tissue-infiltrating lymphocytes was performed by Adaptive Biotechnologies (Seattle, USA). CDR3 sequences were analyzed with Adaptive software to identify TCR clones shared by IgG4-RD and cancer tissues; VDJdb database was used to identify TCR sequences with known antigen specificities. GLIPH2 tool was used to predict clusters of TCRs with the same MHC-restricted peptide antigen specificity. Results: Four patients (3 males and 1 female) were included in this study. Pt1 had pancreatic IgG4-RD and colorectal cancer; Pt2 had lung IgG4-RD and prostate cancer; Pt3 had lung and retroperitoneal IgG4-RD and ovarian cancer; Pt4 had pancreatic IgG4-RD and bladder cancer. IgG4-RD was diagnosed 3 years before or after tumor development. Up to 8.3% of CDR3 sequences in each patient were shared between IgG4-RD and tumor affected tissues but were not identified in control tissues (Figure 1). CDR3 common to IgG4-RD and cancer tissues showed preferred V-J recombination for each patient. HLA-DRB1*11 and DQB1*03 were shared between the four patients. 1.7% to 3.5% of shared TCR in each patient were predicted to recognize CMV, EBV, Influenza, and SARS-CoV-2 specific antigens. The analysis of CDR3 nucleotide sequences identified no common rearrangements across samples from all patients. GLIPH2 identified 15 clusters of motifs predicted to recognize the same antigen shared among the IgG4-RD derived tissues of all patients. Conclusion: The evidence of a TCR CDR3 repertoire shared between IgG4-RD and tumor derived tissues but not control tissues from the same patient strongly supports an immunological response against common antigens occurring in IgG4-RD and cancer. A deeper analyses of clonality on affected tissues will improve our understanding of paraneoplastic IgG4-RD and foster the identification of tumor associated antigens of pathogenic relevance for this disease. REFERENCES: [1] Keller-Sarmiento L, Viapiana N, Lanzillotta M, Batani V, Della-Torre E. Increased Prevalence of Malignancies in Patients with IgG4-Related Disease. Implications for clinical care. Rheumatology. 2024. Acknowledgements: NIL. Disclosure of Interests: None declared.