Lung tumor NF-κB signaling promotes T cell–mediated immune surveillance
Emily L. Hopewell, Weipeng Zhao, William J. Fulp, Crystina C. Bronk, Alexis S. Lopez, Michael Massengill, Scott Antonia, Esteban Celis, Eric B. Haura, Steven A. Enkemann, Dung-Tsa Chen, Amer A. Beg
Emily L. Hopewell, Weipeng Zhao, William J. Fulp, Crystina C. Bronk, Alexis S. Lopez, Michael Massengill, Scott Antonia, Esteban Celis, Eric B. Haura, Steven A. Enkemann, Dung-Tsa Chen, Amer A. Beg
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Research Article Oncology

Lung tumor NF-κB signaling promotes T cell–mediated immune surveillance

Abstract

NF-κB is constitutively activated in many cancer types and is a potential key mediator of tumor-associated inflammation, tumor growth, and metastasis. We investigated the role of cancer cell NF-κB activity in T cell–mediated antitumor responses. In tumors rendered immunogenic by model antigen expression or following administration of antitumor vaccines, we found that high NF-κB activity leads to tumor rejection and/or growth suppression in mice. Using a global RNA expression microarray, we demonstrated that NF-κB enhanced expression of several T cell chemokines, including Ccl2, and decreased CCL2 expression was associated with enhanced tumor growth in a mouse lung cancer model. To investigate NF-κB function in human lung tumors, we identified a gene expression signature in human lung adenocarcinoma cell lines that was associated with NF-κB activity level. In patient tumor samples, overall lung tumor NF-κB activity was strongly associated with T cell infiltration but not with cancer cell proliferation. These results therefore indicate that NF-κB activity mediates immune surveillance and promotes antitumor T cell responses in both murine and human lung cancer.

Authors

Emily L. Hopewell, Weipeng Zhao, William J. Fulp, Crystina C. Bronk, Alexis S. Lopez, Michael Massengill, Scott Antonia, Esteban Celis, Eric B. Haura, Steven A. Enkemann, Dung-Tsa Chen, Amer A. Beg

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Figure 1

Impact of IKKβ-induced NF-κB on tumor rejection.

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Impact of IKKβ-induced NF-κB on tumor rejection. (A) EMSA showing NF-κB ...
(A) EMSA showing NF-κB nuclear levels and (B) RT-PCR showing Cxcl1 expression in LLC-OVA transduced with control MiG, IKK, and MiG treated with TNF-α for 1 and 2 hours. Samples were run in triplicate (mean ± SEM). Tumor growth in C57BL/6 mice inoculated s.c. with (C) nonimmunogenic LLC-MiG and LLC-IKK and (D) immunogenic LLC-OVA-MiG and LLC-OVA-IKK. (E) Impact of immunogenic LLC tumors on peripheral T cells. Tetramer analysis of day-10 OVA-specific CD8 T cells in peripheral blood from naive mice or mice receiving LLC-OVA-MiG or LLC-OVA-IKK cells s.c. Each point represents a single mouse. *P = 0.5485, Student’s t test comparing tetramer+ CD8 T cells between mice receiving LLC-OVA-MiG and LLC-OVA-IKK tumors. (F) C57BL/6 mice received s.c. LLC-OVA-MiG or LLC-OVA-IKK, and tumor growth was monitored. Relative fold increase in tumor volume in mice at day 21 after inoculation compared with day 4 after inoculation. Combined results from 3 independent experiments are shown (n = 11 for both groups). (G) Tumor growth in Rag2–/– mice inoculated s.c. with LLC-OVA-MiG or LLC-OVA-IKK and (H) 129S4/SvJaeJ mice inoculated s.c. with immunogenic LKR-OVA-MiG and LKR-OVA-IKK. (I) C57BL/6 BALB/c F1 mice received s.c. TUBO-MiG or TUBO-IKK. After 5 days, half of the mice in each group received HER2 TriVax. Tumor growth of all mice was calculated at day 21 relative to day 5. Relative growth in vaccinated mice was compared with unvaccinated counterparts. *P = 0.0256, t test with Welch’s correction. Graph shows combined results of 2 independent experiments. (C, D, G, and H) Each line represents a single mouse. (F and I) Each point represents tumor growth from a single mouse.