Expression of NF-κB p50 in Tumor Stroma Limits the Control of Tumors by Radiation Therapy
Open Access
- 28 June 2012
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 7 (6), e39295
- https://doi.org/10.1371/journal.pone.0039295
Abstract
Radiation therapy aims to kill cancer cells with a minimum of normal tissue toxicity. Dying cancer cells have been proposed to be a source of tumor antigens and may release endogenous immune adjuvants into the tumor environment. For these reasons, radiation therapy may be an effective modality to initiate new anti-tumor adaptive immune responses that can target residual disease and distant metastases. However, tumors engender an environment dominated by M2 differentiated tumor macrophages that support tumor invasion, metastases and escape from immune control. In this study, we demonstrate that following radiation therapy of tumors in mice, there is an influx of tumor macrophages that ultimately polarize towards immune suppression. We demonstrate using in vitro models that this polarization is mediated by transcriptional regulation by NFκB p50, and that in mice lacking NFκB p50, radiation therapy is more effective. We propose that despite the opportunity for increased antigen-specific adaptive immune responses, the intrinsic processes of repair following radiation therapy may limit the ability to control residual disease.Keywords
This publication has 53 references indexed in Scilit:
- Protective and pathogenic functions of macrophage subsetsNature Reviews Immunology, 2011
- Acute skeletal muscle injury: CCL2 expression by both monocytes and injured muscle is required for repairThe FASEB Journal, 2011
- Adjuvant Therapy With Agonistic Antibodies to CD134 (OX40) Increases Local Control After Surgical or Radiation Therapy of Cancer in MiceJournal of Immunotherapy, 2010
- Recruitment of Myeloid but not Endothelial Precursor Cells Facilitates Tumor Regrowth after Local IrradiationCancer Research, 2010
- Inhibition of Mac-1 (CD11b/CD18) enhances tumor response to radiation by reducing myeloid cell recruitmentProceedings of the National Academy of Sciences of the United States of America, 2010
- Tolerance and M2 (alternative) macrophage polarization are related processes orchestrated by p50 nuclear factor κBProceedings of the National Academy of Sciences of the United States of America, 2009
- Exploring the full spectrum of macrophage activationNature Reviews Immunology, 2008
- Vascular endothelial growth factor restores delayed tumor progression in tumors depleted of macrophagesMolecular Oncology, 2007
- Toll-like receptor 4–dependent contribution of the immune system to anticancer chemotherapy and radiotherapyNature Medicine, 2007
- Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF.JCI Insight, 1998