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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 4

BAFF increases T cell activation in vivo but also induces an increase in Treg frequency.

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BAFF increases T cell activation in vivo but also induces an increase in...
C57BL/6J mice were challenged with B16F10, followed by treatment with recombinant BAFF (0.5 mg/kg) or vehicle (n = 10 per group) daily beginning on day 7 after tumor implantation. (A) Tumor weights at the time of resection demonstrated significantly decreased tumor weights in the BAFF treatment group. (B) BAFF increases the proportion of B cells and decreases the proportion of CD4+ and CD8+ T cells within the lymph node. (C) BAFF treatment increases central memory cells and decreases naive T cells in the lymph node and TME. (D) BAFF treatment markedly enhances the proportion of CCR6-expressing CD4+ T cells in tumor draining lymph nodes. Expression of CCR6 on CD4+ T cells in lymph nodes parallels an increase in the proportion of Treg, Th1, and Th17 CD4+ T cells within the TME. (E) Treatment of BAFF was associated with the upregulation of IFN-γ+ within a subset of Tregs in the TME, consistent with a “fragile” Treg phenotype. (F) In vivo treatment of B16F10 tumors with recombinant BAFF significantly delays tumor growth. Tumor growth curves for vehicle (blue) and BAFF (red). Mean ± SEM, n = 12 per group. (G) Volcano plot showing significantly upregulated genes in BAFF-treated TIL. n = 3 per group; significance was determined by nSolver’s DE Call function and adjusted using the Benjamini-Yekutieli correction method. Two-tailed unpaired t test were used to compare vehicle and BAFF group weights and cell phenotypes; *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

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