Canonical NFκB signaling in myeloid cells is required for the glioblastoma growth

Bhagelu Ram Achyut, Kartik Angara, Meenu Jain, Thaiz Ferraz Borin, Mohammad H. Rashid, A. S.M. Iskander, Roxan Ara, Ravindra Bharat Kolhe, Shelby Howard, Natasha Venugopal, Paulo C. Rodriguez, Jennifer Webster Bradford, Ali Syed Arbab

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Tumor development and therapeutic resistance are linked with tumor-Associated macrophage (TAM) and myeloid-derived suppressor cell (MDSC) infiltration in tumors via chemokine axis. Chemokine expression, which determines the pro or anti-inflammatory status of myeloid cells, are partly regulated by the nuclear factor-kappa B (NF-κB) pathway. Here, we identified that conditional deletion of canonical NF-κB signaling (p65) in myeloid cells inhibited syngeneic glioblastoma (GBM) through decreased CD45 infiltration in tumors, as characterized by decreased TAMs (CD206+) and MDSCs (Gr1+ CD11b+), increased dendritic cells (CD86+) and cytotoxic T cells (CD8+) in the p65 knockout (KO) mice. Proinflammatory cytokines (IFNγ, MCP1, MIP1α, and TNFα) and myeloid differentiation factor (Endoglin) were increased in myeloid cells from p65 KO tumor, which demonstrated an influence on CD8+T cell proliferation. In contrast, p65KO athymic chimeric mice with human GBM, failed to inhibit tumor growth, confirming the contribution of T cells in an immune competent model. The analysis of human datasets and GBM tumors revealed higher expression of p65 in GBM-Associated CD68+ macrophages compared to neighboring stroma. Thus, canonical NF-κB signaling has an anti-inflammatory role and is required for macrophage polarization, immune suppression, and GBM growth. Combining an NF-κB inhibitor with standard therapy could improve antitumor immunity in GBM.

Original languageEnglish (US)
Article number13754
JournalScientific Reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

Fingerprint

Myeloid Cells
Glioblastoma
NF-kappa B
Growth
Neoplasms
Macrophages
T-Lymphocytes
Chemokines
Anti-Inflammatory Agents
Nude Mice
Knockout Mice
Dendritic Cells
Immunity
Cell Proliferation
Cytokines
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

Canonical NFκB signaling in myeloid cells is required for the glioblastoma growth. / Achyut, Bhagelu Ram; Angara, Kartik; Jain, Meenu; Borin, Thaiz Ferraz; Rashid, Mohammad H.; Iskander, A. S.M.; Ara, Roxan; Kolhe, Ravindra Bharat; Howard, Shelby; Venugopal, Natasha; Rodriguez, Paulo C.; Bradford, Jennifer Webster; Arbab, Ali Syed.

In: Scientific Reports, Vol. 7, No. 1, 13754, 01.12.2017.

Research output: Contribution to journalArticle

Achyut, BR, Angara, K, Jain, M, Borin, TF, Rashid, MH, Iskander, ASM, Ara, R, Kolhe, RB, Howard, S, Venugopal, N, Rodriguez, PC, Bradford, JW & Arbab, AS 2017, 'Canonical NFκB signaling in myeloid cells is required for the glioblastoma growth', Scientific Reports, vol. 7, no. 1, 13754. https://doi.org/10.1038/s41598-017-14079-4
Achyut, Bhagelu Ram ; Angara, Kartik ; Jain, Meenu ; Borin, Thaiz Ferraz ; Rashid, Mohammad H. ; Iskander, A. S.M. ; Ara, Roxan ; Kolhe, Ravindra Bharat ; Howard, Shelby ; Venugopal, Natasha ; Rodriguez, Paulo C. ; Bradford, Jennifer Webster ; Arbab, Ali Syed. / Canonical NFκB signaling in myeloid cells is required for the glioblastoma growth. In: Scientific Reports. 2017 ; Vol. 7, No. 1.
@article{700876c8d7c340138523292f32836c95,
title = "Canonical NFκB signaling in myeloid cells is required for the glioblastoma growth",
abstract = "Tumor development and therapeutic resistance are linked with tumor-Associated macrophage (TAM) and myeloid-derived suppressor cell (MDSC) infiltration in tumors via chemokine axis. Chemokine expression, which determines the pro or anti-inflammatory status of myeloid cells, are partly regulated by the nuclear factor-kappa B (NF-κB) pathway. Here, we identified that conditional deletion of canonical NF-κB signaling (p65) in myeloid cells inhibited syngeneic glioblastoma (GBM) through decreased CD45 infiltration in tumors, as characterized by decreased TAMs (CD206+) and MDSCs (Gr1+ CD11b+), increased dendritic cells (CD86+) and cytotoxic T cells (CD8+) in the p65 knockout (KO) mice. Proinflammatory cytokines (IFNγ, MCP1, MIP1α, and TNFα) and myeloid differentiation factor (Endoglin) were increased in myeloid cells from p65 KO tumor, which demonstrated an influence on CD8+T cell proliferation. In contrast, p65KO athymic chimeric mice with human GBM, failed to inhibit tumor growth, confirming the contribution of T cells in an immune competent model. The analysis of human datasets and GBM tumors revealed higher expression of p65 in GBM-Associated CD68+ macrophages compared to neighboring stroma. Thus, canonical NF-κB signaling has an anti-inflammatory role and is required for macrophage polarization, immune suppression, and GBM growth. Combining an NF-κB inhibitor with standard therapy could improve antitumor immunity in GBM.",
author = "Achyut, {Bhagelu Ram} and Kartik Angara and Meenu Jain and Borin, {Thaiz Ferraz} and Rashid, {Mohammad H.} and Iskander, {A. S.M.} and Roxan Ara and Kolhe, {Ravindra Bharat} and Shelby Howard and Natasha Venugopal and Rodriguez, {Paulo C.} and Bradford, {Jennifer Webster} and Arbab, {Ali Syed}",
year = "2017",
month = "12",
day = "1",
doi = "10.1038/s41598-017-14079-4",
language = "English (US)",
volume = "7",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - Canonical NFκB signaling in myeloid cells is required for the glioblastoma growth

AU - Achyut, Bhagelu Ram

AU - Angara, Kartik

AU - Jain, Meenu

AU - Borin, Thaiz Ferraz

AU - Rashid, Mohammad H.

AU - Iskander, A. S.M.

AU - Ara, Roxan

AU - Kolhe, Ravindra Bharat

AU - Howard, Shelby

AU - Venugopal, Natasha

AU - Rodriguez, Paulo C.

AU - Bradford, Jennifer Webster

AU - Arbab, Ali Syed

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Tumor development and therapeutic resistance are linked with tumor-Associated macrophage (TAM) and myeloid-derived suppressor cell (MDSC) infiltration in tumors via chemokine axis. Chemokine expression, which determines the pro or anti-inflammatory status of myeloid cells, are partly regulated by the nuclear factor-kappa B (NF-κB) pathway. Here, we identified that conditional deletion of canonical NF-κB signaling (p65) in myeloid cells inhibited syngeneic glioblastoma (GBM) through decreased CD45 infiltration in tumors, as characterized by decreased TAMs (CD206+) and MDSCs (Gr1+ CD11b+), increased dendritic cells (CD86+) and cytotoxic T cells (CD8+) in the p65 knockout (KO) mice. Proinflammatory cytokines (IFNγ, MCP1, MIP1α, and TNFα) and myeloid differentiation factor (Endoglin) were increased in myeloid cells from p65 KO tumor, which demonstrated an influence on CD8+T cell proliferation. In contrast, p65KO athymic chimeric mice with human GBM, failed to inhibit tumor growth, confirming the contribution of T cells in an immune competent model. The analysis of human datasets and GBM tumors revealed higher expression of p65 in GBM-Associated CD68+ macrophages compared to neighboring stroma. Thus, canonical NF-κB signaling has an anti-inflammatory role and is required for macrophage polarization, immune suppression, and GBM growth. Combining an NF-κB inhibitor with standard therapy could improve antitumor immunity in GBM.

AB - Tumor development and therapeutic resistance are linked with tumor-Associated macrophage (TAM) and myeloid-derived suppressor cell (MDSC) infiltration in tumors via chemokine axis. Chemokine expression, which determines the pro or anti-inflammatory status of myeloid cells, are partly regulated by the nuclear factor-kappa B (NF-κB) pathway. Here, we identified that conditional deletion of canonical NF-κB signaling (p65) in myeloid cells inhibited syngeneic glioblastoma (GBM) through decreased CD45 infiltration in tumors, as characterized by decreased TAMs (CD206+) and MDSCs (Gr1+ CD11b+), increased dendritic cells (CD86+) and cytotoxic T cells (CD8+) in the p65 knockout (KO) mice. Proinflammatory cytokines (IFNγ, MCP1, MIP1α, and TNFα) and myeloid differentiation factor (Endoglin) were increased in myeloid cells from p65 KO tumor, which demonstrated an influence on CD8+T cell proliferation. In contrast, p65KO athymic chimeric mice with human GBM, failed to inhibit tumor growth, confirming the contribution of T cells in an immune competent model. The analysis of human datasets and GBM tumors revealed higher expression of p65 in GBM-Associated CD68+ macrophages compared to neighboring stroma. Thus, canonical NF-κB signaling has an anti-inflammatory role and is required for macrophage polarization, immune suppression, and GBM growth. Combining an NF-κB inhibitor with standard therapy could improve antitumor immunity in GBM.

UR - http://www.scopus.com/inward/record.url?scp=85032204982&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85032204982&partnerID=8YFLogxK

U2 - 10.1038/s41598-017-14079-4

DO - 10.1038/s41598-017-14079-4

M3 - Article

C2 - 29062041

AN - SCOPUS:85032204982

VL - 7

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 13754

ER -