The BAFF-APRIL System in Cancer

SIMPLE SUMMARY: The ligands BAFF and APRIL and their cognate receptors are critical for the differentiation, survival, and function of B cells and, as such, the maintenance of humoral immunity. The BAFF-APRIL system also modulates, either directly or indirectly, the function of other immune and non-immune cells. Clinical and experimental evidence suggests that aberrant BAFF-APRIL production impairs immune homeostasis, breaks immune tolerance, and aggravates cancer cell proliferation and invasion. Here, we have reviewed the latest understanding of the role of the BAFF-APRIL system in cancer. Greater clarity on the exact involvement of these two factors in cancer will pave the way for identifying new biomarkers for early diagnosis and developing novel therapeutic strategies. ABSTRACT: B cell-activating factor (BAFF; also known as CD257, TNFSF13B, BLyS) and a proliferation-inducing ligand (APRIL; also known as CD256, TNFSF13) belong to the tumor necrosis factor (TNF) family. BAFF was initially discovered as a B-cell survival factor, whereas APRIL was first identified as a protein highly expressed in various cancers. These discoveries were followed by over two decades of extensive research effort, which identified overlapping signaling cascades between BAFF and APRIL, controlling immune homeostasis in health and driving pathogenesis in autoimmunity and cancer, the latter being the focus of this review. High levels of BAFF, APRIL, and their receptors have been detected in different cancers and found to be associated with disease severity and treatment response. Here, we have summarized the role of the BAFF-APRIL system in immune cell differentiation and immune tolerance and detailed its pathogenic functions in hematological and solid cancers. We also highlight the emerging therapeutics targeting the BAFF-APRIL system in different cancer types.