Critical and distinct roles of cell type–specific NF-κB2 in lung cancer
Fan Sun, Yadong Xiao, Steven D. Shapiro, Zhaoxia Qu, Gutian Xiao
Fan Sun, Yadong Xiao, Steven D. Shapiro, Zhaoxia Qu, Gutian Xiao
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Research Article Oncology

Critical and distinct roles of cell type–specific NF-κB2 in lung cancer

Abstract

Different from the well-studied canonical NF-κB member RelA, the role of the noncanonical NF-κB member NF-κB2 in solid tumors, and lung cancer in particular, is poorly understood. Here we report that in contrast to the tumor-promoting role of RelA, NF-κB2 intrinsic to lung epithelial and tumor cells had no marked effect on lung tumorigenesis and progression. On the other hand, NF-κB2 limited dendritic cell number and activation in the lung but protected lung macrophages and drove them to promote lung cancer through controlling activation of noncanonical and canonical NF-κB, respectively. NF-κB2 was also required for B cell maintenance and T cell activation. The antitumor activity of lymphocyte NF-κB2 was dominated by the protumor function of myeloid NF-κB2; thus, NF-κB2 has an overall tumor-promoting activity. These studies reveal a cell type–dependent role for NF-κB2 in lung cancer and help understand the complexity of NF-κB action and lung cancer pathogenesis for better design of NF-κB–targeted therapy against this deadliest cancer.

Authors

Fan Sun, Yadong Xiao, Steven D. Shapiro, Zhaoxia Qu, Gutian Xiao

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Figure 5

Increased T cell activation activity of DCs induced by NF-κB2 deletion in lung tumorigenesis.

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Increased T cell activation activity of DCs induced by NF-κB2 deletion i...
(A) Flow cytometry analysis showing increased DCs in the lung of urethane-treated NF-κB2–deficient mice (n = 3) compared with WT mice (n = 5). (B) Flow cytometry analysis showing increased MHC-II (WT, n = 5; NF-κB2–/–, n = 3), CD80 (WT, n = 4; NF-κB2–/–, n = 3), and CD86 (WT, n = 4; NF-κB2–/–, n = 3) in DCs, markers of DC activation, in the lung of urethane-treated NF-κB2–deficient mice. (C) In vitro T cell activation analysis showing increased ability of NF-κB2–deficient DCs in activating CD4+ T cells (n = 4). (D) In vitro T cell activation showing increased ability of NF-κB2–deficient DCs in activating CD8+ T cells (n = 4). (E) In vitro tumor cell killing assays showing increased ability of NF-κB2–deficient DCs in inducing the tumoricidal activity of T cells (n = 3). (F) IB of nuclear fraction showing increased RelB activation in NF-κB2–deficient DCs induced by TCM. Data are presented as mean ± SEM. *P < 0.05; **P < 0.01 by 2-tailed, unpaired Student’s t test (A, B, and E) or ordinary 1-way ANOVA (C and D). NS, not statistically significant.