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Effects of B cell–activating factor on tumor immunity
Mark Yarchoan, … , Todd D. Armstrong, Elizabeth M. Jaffee
Mark Yarchoan, … , Todd D. Armstrong, Elizabeth M. Jaffee
Published May 21, 2020
Citation Information: JCI Insight. 2020;5(10):e136417. https://doi.org/10.1172/jci.insight.136417.
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Research Article Immunology Oncology

Effects of B cell–activating factor on tumor immunity

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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.

Authors

Mark Yarchoan, Won Jin Ho, Aditya Mohan, Yajas Shah, Teena Vithayathil, James Leatherman, Lauren Dennison, Neeha Zaidi, Sudipto Ganguly, Skylar Woolman, Kayla Cruz, Todd D. Armstrong, Elizabeth M. Jaffee

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Figure 3

BAFF augments Th1 responses and promotes antitumor immunity, but also has distinct immunoregulatory functions.

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BAFF augments Th1 responses and promotes antitumor immunity, but also ha...
(A) Uniform manifold approximation plot (UMAP), a dimensionality reduction technique to visualize similar cell proteomic characteristics in 2 dimensions, shows clustering results of 16 spleen samples (8 biological replicates for each of the 2 experimental arms) analyzed by mass cytometry. A total of 2000 events per sample is shown. Each color represents a specific immune cell type, as annotated based on marker intensity profiles. Color legend is shown with B. (B) Immune cell composition within each of the spleen samples are shown in stacked bar graphs as a percentage of CD45+ cells. (C) BAFF treatment increases the proportion of B cells in the spleen, while decreasing G-MDSC, NK, and Th cell populations. (D) Of the Th cell fraction, BAFF treatment increases the proportion of CD44+ cells, while decreasing the proportion of Tregs. (E) BAFF treatment increases the mean signal intensity of PD-1 in Tregs taken from the spleen. (F) Mass intensity heatmaps for each of the 2 immune markers, CD40 and PD-L1, are superimposed onto the UMAP representation of the cell clusters, as shown in A for the 2 experimental groups, vehicle- and BAFF-treated. (G) BAFF treatment affects B cells by increasing the proportion of B cells expressing CD1d, CD25, CD40, CD5, GZMB, Lag3, PD-L1, and RORγt (statistically significant changes). (H) BAFF treatment affects CD8+ cytotoxic T (Tc) cells by increasing the proportion of Tc cells expressing CD40 and CD69. (I) BAFF treatment affects Th cells by increasing the proportion of Th cells expressing CD40, CD69, ICOS, Lag3, PD-1, and PD-L1, while decreasing the proportion of cells expressing CD27. Two-tailed unpaired t tests were used to compare vehicle and BAFF groups; *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

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