Abstract 2217: Commensal bacteria are internal triggers of chronic inflammation and B-cell lymphoma development in myeloid cell-specific TRAF3-deficient mice

Abstract Myeloid cells are central players in innate immunity and inflammation. Their function is regulated by the adaptor protein TRAF3. We previously reported that aging myeloid cell-specific TRAF3-deficient (M-Traf3-/-) mice spontaneously develop chronic inflammation and B-cell lymphoma (BCL). In the present study, we aimed to identify the internal trigger of this disease phenotype in these mice. We first detected gut dysbiosis and transmigration of commensal bacteria to the liver in aging M-Traf3-/- mice. Interestingly, depletion of commensal bacteria using antibiotics effectively prevented chronic inflammation and BCL development in these mice. Systemic IgG responses against commensal bacteria were induced and the IgH CDR3 sequences of malignant B-cell clones of M-Traf3/- mice showed high homology to prevalent bacteria-reactive Ig clonotypes. Furthermore, M-Traf3-/- mice with BCL exhibited high titers of antibodies against commensal bacteria in their serum. Together, our findings suggest that commensal bacteria dysbiosis and transmigration can promote chronic inflammation and BCL development in individuals with compromised innate immunity. Accordingly, targeting relevant commensal bacteria may serve as a therapeutic strategy for preventing and treating chronic inflammation and BCL in these patients. This study was supported by the National Cancer Institute Grant R01CA293055, the National Institute of Allergy and Infectious Diseases Grant R21AI128264, a HealthAdvance Award, the Grossman Innovation Prize, and a New Jersey Commission on Cancer Research (NJCCR) grant DCHS19CRF005. Citation Format: Jaeyong Jung, Sining Zhu, Almin I. Lalani, Judith Shakarchi, Brygida Matracz, Guojun G. Wu, Wei-Xing Zong, Liping Zhao, Ping Xie. Commensal bacteria are internal triggers of chronic inflammation and B-cell lymphoma development in myeloid cell-specific TRAF3-deficient mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2217.