Abstract
Immunotherapies that modulate T cell function have been firmly established as a pillar of cancer therapy, whereas the potential for B cells in the antitumor immune response is less established. B cell-activating factor (BAFF) is a B cell-activating cytokine belonging to the TNF ligand family that has been associated with autoimmunity, but little is known about its effects on cancer immunity. We find that BAFF upregulates multiple B cell costimulatory molecules; augments IL-12a expression, consistent with Be-1 lineage commitment; and enhances B cell antigen-presentation to CD4+ Th cells in vitro. In a syngeneic mouse model of melanoma, BAFF upregulates B cell CD40 and PD-L1 expression; it also modulates T cell function through increased T cell activation and TH1 polarization, enhanced expression of the proinflammatory leukocyte trafficking chemokine CCR6, and promotion of a memory phenotype, leading to enhanced antitumor immunity. Similarly, adjuvant BAFF promotes a memory phenotype of T cells in vaccine-draining lymph nodes and augments the antitumor efficacy of whole cell vaccines. BAFF also has distinct immunoregulatory functions, promoting the expansion of CD4+Foxp3+ Tregs in the spleen and tumor microenvironment (TME). Human melanoma data from The Cancer Genome Atlas (TCGA) demonstrate that BAFF expression is positively associated with overall survival and a TH1/IFN-γ gene signature. These data support a potential role for BAFF signaling as a cancer immunotherapy.
Highlights
Immunotherapies that modulate T cell function have been firmly established as a pillar of cancer therapy, whereas the potential for B cells in the antitumor immune response is not well established
We find that BAFF has distinct effects on B and T cells that contribute to antitumor immunity (Figure 7)
BAFF activates B cells expressing high levels of costimulatory molecules (CD40, ICOSL), augments antigen presentation to CD4+ T cells through increased expression of MHC class II (MHCII), and increases IL-12 expression to promote the differentiation of TH1 cells and T cell memory
Summary
Immunotherapies that modulate T cell function have been firmly established as a pillar of cancer therapy, whereas the potential for B cells in the antitumor immune response is not well established. Beyond their well-defined role as antibody-producing cells, B cells contribute to immune regulation in a number of different ways. Activated B cells express high levels of MHC class II (MHCII) and serve as the predominant APCs to initiate CD4+ T cell responses under some physiological conditions [3,4,5,6,7]. In addition to inducing Ag-specific T cell priming in vivo, B cells can express costimulatory signals required for CD4+ T cell clonal expansion and can break CD4+ T cell tolerance in vivo [4]
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