NF-κB regulates GDF-15 to suppress macrophage surveillance during early tumor development

Nivedita M. Ratnam, Jennifer M. Peterson, Erin E. Talbert, Katherine J. Ladner, Priyani V. Rajasekera, Carl R. Schmidt, Mary E. Dillhoff, Benjamin J Swanson, Ericka Haverick, Raleigh D. Kladney, Terence M. Williams, Gustavo W. Leone, David J. Wang, Denis C. Guttridge

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Macrophages are attracted to developing tumors and can participate in immune surveillance to eliminate neoplastic cells. In response, neoplastic cells utilize NF-κB to suppress this killing activity, but the mechanisms underlying their self-protection remain unclear. Here, we report that this dynamic interaction between tumor cells and macrophages is integrally linked by a soluble factor identified as growth and differentiation factor 15 (GDF-15). In vitro, tumor-derived GDF-15 signals in macrophages to suppress their proapoptotic activity by inhibiting TNF and nitric oxide (NO) production. In vivo, depletion of GDF-15 in Ras-driven tumor xenografts and in an orthotopic model of pancreatic cancer delayed tumor development. This delay correlated with increased infiltrating antitumor macrophages. Further, production of GDF-15 is directly regulated by NF-κB, and the colocalization of activated NF-κB and GDF-15 in epithelial ducts of human pancreatic adenocarcinoma supports the importance of this observation. Mechanistically, we found that GDF-15 suppresses macrophage activity by inhibiting TGF-β-activated kinase (TAK1) signaling to NF-κB, thereby blocking synthesis of TNF and NO. Based on these results, we propose that the NF-κB/GDF-15 regulatory axis is important for tumor cells in evading macrophage immune surveillance during the early stages of tumorigenesis.

Original languageEnglish (US)
Pages (from-to)3796-3809
Number of pages14
JournalJournal of Clinical Investigation
Volume127
Issue number10
DOIs
StatePublished - Oct 2 2017

Fingerprint

Growth Differentiation Factor 15
Macrophages
Neoplasms
Nitric Oxide
Pancreatic Ducts
Pancreatic Neoplasms
Heterografts
Carcinogenesis
Adenocarcinoma
Phosphotransferases

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Ratnam, N. M., Peterson, J. M., Talbert, E. E., Ladner, K. J., Rajasekera, P. V., Schmidt, C. R., ... Guttridge, D. C. (2017). NF-κB regulates GDF-15 to suppress macrophage surveillance during early tumor development. Journal of Clinical Investigation, 127(10), 3796-3809. https://doi.org/10.1172/JCI91561

NF-κB regulates GDF-15 to suppress macrophage surveillance during early tumor development. / Ratnam, Nivedita M.; Peterson, Jennifer M.; Talbert, Erin E.; Ladner, Katherine J.; Rajasekera, Priyani V.; Schmidt, Carl R.; Dillhoff, Mary E.; Swanson, Benjamin J; Haverick, Ericka; Kladney, Raleigh D.; Williams, Terence M.; Leone, Gustavo W.; Wang, David J.; Guttridge, Denis C.

In: Journal of Clinical Investigation, Vol. 127, No. 10, 02.10.2017, p. 3796-3809.

Research output: Contribution to journalArticle

Ratnam, NM, Peterson, JM, Talbert, EE, Ladner, KJ, Rajasekera, PV, Schmidt, CR, Dillhoff, ME, Swanson, BJ, Haverick, E, Kladney, RD, Williams, TM, Leone, GW, Wang, DJ & Guttridge, DC 2017, 'NF-κB regulates GDF-15 to suppress macrophage surveillance during early tumor development', Journal of Clinical Investigation, vol. 127, no. 10, pp. 3796-3809. https://doi.org/10.1172/JCI91561
Ratnam NM, Peterson JM, Talbert EE, Ladner KJ, Rajasekera PV, Schmidt CR et al. NF-κB regulates GDF-15 to suppress macrophage surveillance during early tumor development. Journal of Clinical Investigation. 2017 Oct 2;127(10):3796-3809. https://doi.org/10.1172/JCI91561
Ratnam, Nivedita M. ; Peterson, Jennifer M. ; Talbert, Erin E. ; Ladner, Katherine J. ; Rajasekera, Priyani V. ; Schmidt, Carl R. ; Dillhoff, Mary E. ; Swanson, Benjamin J ; Haverick, Ericka ; Kladney, Raleigh D. ; Williams, Terence M. ; Leone, Gustavo W. ; Wang, David J. ; Guttridge, Denis C. / NF-κB regulates GDF-15 to suppress macrophage surveillance during early tumor development. In: Journal of Clinical Investigation. 2017 ; Vol. 127, No. 10. pp. 3796-3809.
@article{d75735de23ca46c7b927c6054fdf9ab4,
title = "NF-κB regulates GDF-15 to suppress macrophage surveillance during early tumor development",
abstract = "Macrophages are attracted to developing tumors and can participate in immune surveillance to eliminate neoplastic cells. In response, neoplastic cells utilize NF-κB to suppress this killing activity, but the mechanisms underlying their self-protection remain unclear. Here, we report that this dynamic interaction between tumor cells and macrophages is integrally linked by a soluble factor identified as growth and differentiation factor 15 (GDF-15). In vitro, tumor-derived GDF-15 signals in macrophages to suppress their proapoptotic activity by inhibiting TNF and nitric oxide (NO) production. In vivo, depletion of GDF-15 in Ras-driven tumor xenografts and in an orthotopic model of pancreatic cancer delayed tumor development. This delay correlated with increased infiltrating antitumor macrophages. Further, production of GDF-15 is directly regulated by NF-κB, and the colocalization of activated NF-κB and GDF-15 in epithelial ducts of human pancreatic adenocarcinoma supports the importance of this observation. Mechanistically, we found that GDF-15 suppresses macrophage activity by inhibiting TGF-β-activated kinase (TAK1) signaling to NF-κB, thereby blocking synthesis of TNF and NO. Based on these results, we propose that the NF-κB/GDF-15 regulatory axis is important for tumor cells in evading macrophage immune surveillance during the early stages of tumorigenesis.",
author = "Ratnam, {Nivedita M.} and Peterson, {Jennifer M.} and Talbert, {Erin E.} and Ladner, {Katherine J.} and Rajasekera, {Priyani V.} and Schmidt, {Carl R.} and Dillhoff, {Mary E.} and Swanson, {Benjamin J} and Ericka Haverick and Kladney, {Raleigh D.} and Williams, {Terence M.} and Leone, {Gustavo W.} and Wang, {David J.} and Guttridge, {Denis C.}",
year = "2017",
month = "10",
day = "2",
doi = "10.1172/JCI91561",
language = "English (US)",
volume = "127",
pages = "3796--3809",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "10",

}

TY - JOUR

T1 - NF-κB regulates GDF-15 to suppress macrophage surveillance during early tumor development

AU - Ratnam, Nivedita M.

AU - Peterson, Jennifer M.

AU - Talbert, Erin E.

AU - Ladner, Katherine J.

AU - Rajasekera, Priyani V.

AU - Schmidt, Carl R.

AU - Dillhoff, Mary E.

AU - Swanson, Benjamin J

AU - Haverick, Ericka

AU - Kladney, Raleigh D.

AU - Williams, Terence M.

AU - Leone, Gustavo W.

AU - Wang, David J.

AU - Guttridge, Denis C.

PY - 2017/10/2

Y1 - 2017/10/2

N2 - Macrophages are attracted to developing tumors and can participate in immune surveillance to eliminate neoplastic cells. In response, neoplastic cells utilize NF-κB to suppress this killing activity, but the mechanisms underlying their self-protection remain unclear. Here, we report that this dynamic interaction between tumor cells and macrophages is integrally linked by a soluble factor identified as growth and differentiation factor 15 (GDF-15). In vitro, tumor-derived GDF-15 signals in macrophages to suppress their proapoptotic activity by inhibiting TNF and nitric oxide (NO) production. In vivo, depletion of GDF-15 in Ras-driven tumor xenografts and in an orthotopic model of pancreatic cancer delayed tumor development. This delay correlated with increased infiltrating antitumor macrophages. Further, production of GDF-15 is directly regulated by NF-κB, and the colocalization of activated NF-κB and GDF-15 in epithelial ducts of human pancreatic adenocarcinoma supports the importance of this observation. Mechanistically, we found that GDF-15 suppresses macrophage activity by inhibiting TGF-β-activated kinase (TAK1) signaling to NF-κB, thereby blocking synthesis of TNF and NO. Based on these results, we propose that the NF-κB/GDF-15 regulatory axis is important for tumor cells in evading macrophage immune surveillance during the early stages of tumorigenesis.

AB - Macrophages are attracted to developing tumors and can participate in immune surveillance to eliminate neoplastic cells. In response, neoplastic cells utilize NF-κB to suppress this killing activity, but the mechanisms underlying their self-protection remain unclear. Here, we report that this dynamic interaction between tumor cells and macrophages is integrally linked by a soluble factor identified as growth and differentiation factor 15 (GDF-15). In vitro, tumor-derived GDF-15 signals in macrophages to suppress their proapoptotic activity by inhibiting TNF and nitric oxide (NO) production. In vivo, depletion of GDF-15 in Ras-driven tumor xenografts and in an orthotopic model of pancreatic cancer delayed tumor development. This delay correlated with increased infiltrating antitumor macrophages. Further, production of GDF-15 is directly regulated by NF-κB, and the colocalization of activated NF-κB and GDF-15 in epithelial ducts of human pancreatic adenocarcinoma supports the importance of this observation. Mechanistically, we found that GDF-15 suppresses macrophage activity by inhibiting TGF-β-activated kinase (TAK1) signaling to NF-κB, thereby blocking synthesis of TNF and NO. Based on these results, we propose that the NF-κB/GDF-15 regulatory axis is important for tumor cells in evading macrophage immune surveillance during the early stages of tumorigenesis.

UR - http://www.scopus.com/inward/record.url?scp=85030548987&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85030548987&partnerID=8YFLogxK

U2 - 10.1172/JCI91561

DO - 10.1172/JCI91561

M3 - Article

C2 - 28891811

AN - SCOPUS:85030548987

VL - 127

SP - 3796

EP - 3809

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 10

ER -