Abstract A054: Commensal bacteria drive B-cell lymphoma development and progression in the presence of intact innate immunity

Abstract

We recently reported that commensal bacteria drive B-cell lymphomagenesis in the setting of innate immunodeficiency. Here we present evidence demonstrating that commensal bacteria promote B-cell lymphoma (BCL) development and progression in a mouse model with intact innate immunity, B-cell-specific TRAF3-deficient (B-Traf3 -/-) mice. Specific deletion of the tumor suppressor TRAF3 from B lymphocytes leads to spontaneous development of splenic marginal zone lymphoma (MZL) and B1 BCL. We found that depletion of the gut microbiota using broad-spectrum antibiotics significantly improved survival, attenuated BCL development, and inhibited BCL metastasis in B-Traf3-/- mice. Interestingly, the CDR3 sequences of malignant B-cell clones in B-Traf3 -/- mice exhibited high homology to prevalent bacteria-reactive immunoglobulin (Ig) clonotypes. B-Traf3 -/- mice with BCL exhibited markedly elevated serum antibody titers against commensal bacterial antigens, which were significantly reduced following antibiotic treatment. Furthermore, we demonstrated that sterile commensal bacterial antigens induced surface B-cell receptor (BCR) internalization and Btk phosphorylation in splenic BCL cells from B-Traf3 -/- mice. However, in contrast to mice with compromised innate immunity, we did not detect overt transmigration of commensal bacteria to the liver or spleen in B-Traf3 -/- mice with BCL. Together, our findings indicate that in the absence of commensal bacterial transmigration or overt infection, commensal bacteria-derived antigens can engage BCR signaling and promote BCL development and progression. Our findings suggest a broad role for the gut microbiota and their antigens in driving B-cell lymphomagenesis. This study was supported by the National Cancer Institute Grant R01CA293055, a ROI-HealthAdvance Award and NHLBI U01HL150852, the Grossman Innovation Prize, NCI P30CA072720, and a New Jersey Commission on Cancer Research (NJCCR) grant DCHS19CRF005.