NF-κB p50-deficient immature myeloid cell (p50-IMC) adoptive transfer slows the growth of murine prostate and pancreatic ductal carcinoma
BackgroundMacrophages and dendritic cells lacking the transcription factor nuclear factor kappa B p50 are skewed toward a proinflammatory phenotype, with increased cytokine expression and enhanced T cell activation; additionally, murine melanoma, fibrosarcoma, colon carcinoma, and glioblastoma grow...
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doaj-4bfc460d3160438d8f6ead5716dfadaf2021-07-19T12:00:11ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-06-018110.1136/jitc-2019-000244NF-κB p50-deficient immature myeloid cell (p50-IMC) adoptive transfer slows the growth of murine prostate and pancreatic ductal carcinomaTheresa Barberi0Rahul Suresh1Alan D Friedman2David J BarakatKenneth J PientaAff504 grid.21107.350000000121719311Johns Hopkins University Baltimore MD USA Aff504 grid.21107.350000000121719311Johns Hopkins University Baltimore MD USAAff1 grid.21107.350000000121719311Johns Hopkins University School of Medicine Baltimore MD USABackgroundMacrophages and dendritic cells lacking the transcription factor nuclear factor kappa B p50 are skewed toward a proinflammatory phenotype, with increased cytokine expression and enhanced T cell activation; additionally, murine melanoma, fibrosarcoma, colon carcinoma, and glioblastoma grow slower in p50−/− mice. We therefore evaluated the efficacy of p50-negative immature myeloid cells (p50-IMCs) adoptively transferred into tumor-bearing hosts. Immature cells were used to maximize tumor localization, and pretreatment with 5-fluorouracil (5FU) was examined due to its potential to impair marrow production of myeloid cells, to target tumor myeloid cells and to release tumor neoantigens.MethodsWild-type (WT)-IMC or p50-IMC were generated by culturing lineage-negative marrow cells from WT or p50−/− mice in media containing thrombopoietin, stem cell factor and Flt3 ligand for 6 days followed by monocyte colony-stimulating factor for 1 day on ultralow attachment plates. Mice inoculated with Hi-Myc prostate cancer (PCa) cells or K-RasG12D pancreatic ductal carcinoma (PDC)-luciferase cells received 5FU followed 5 days later by three doses of 107 immature myeloid cells (IMC) every 3–4 days.ResultsPCa cells grew slower in p50−/− mice, and absence of host p50 prolonged the survival of mice inoculated orthotopically with PDC cells. IMC from Cytomegalovirus (CMV)-luciferase mice localized to tumor, nodes, spleen, marrow, and lung. 5FU followed by p50-IMC slowed PCa and PDC tumor growth, ~3-fold on average, in contrast to 5FU followed by WT-IMC, 5FU alone or p50-IMC alone. Slowed tumor growth was evident for 93% of PCa but only 53% of PDC tumors; we therefore focused on PCa for additional IMC analyses. In PCa, p50-IMC matured into F4/80+ macrophages, as well as CD11b+F4/80−CD11c+ conventional dendritic cells (cDCs). In both tumor and draining lymph nodes, p50-IMC generated more macrophages and cDCs than WT-IMC. Activated tumor CD8+ T cells were increased fivefold by p50-IMC compared with WT-IMC, and antibody-mediated CD8+ T cell depletion obviated slower tumor growth induced by 5FU followed by p50-IMC.Conclusions5FU followed by p50-IMC slows the growth of murine prostate and pancreatic carcinoma and depends on CD8+ T cell activation. Deletion of p50 in patient-derived marrow CD34+ cells and subsequent production of IMC for adoptive transfer may contribute to the therapy of these and additional cancers.https://jitc.bmj.com/content/8/1/e000244.full |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Theresa Barberi Rahul Suresh Alan D Friedman David J Barakat Kenneth J Pienta |
spellingShingle |
Theresa Barberi Rahul Suresh Alan D Friedman David J Barakat Kenneth J Pienta NF-κB p50-deficient immature myeloid cell (p50-IMC) adoptive transfer slows the growth of murine prostate and pancreatic ductal carcinoma Journal for ImmunoTherapy of Cancer |
author_facet |
Theresa Barberi Rahul Suresh Alan D Friedman David J Barakat Kenneth J Pienta |
author_sort |
Theresa Barberi |
title |
NF-κB p50-deficient immature myeloid cell (p50-IMC) adoptive transfer slows the growth of murine prostate and pancreatic ductal carcinoma |
title_short |
NF-κB p50-deficient immature myeloid cell (p50-IMC) adoptive transfer slows the growth of murine prostate and pancreatic ductal carcinoma |
title_full |
NF-κB p50-deficient immature myeloid cell (p50-IMC) adoptive transfer slows the growth of murine prostate and pancreatic ductal carcinoma |
title_fullStr |
NF-κB p50-deficient immature myeloid cell (p50-IMC) adoptive transfer slows the growth of murine prostate and pancreatic ductal carcinoma |
title_full_unstemmed |
NF-κB p50-deficient immature myeloid cell (p50-IMC) adoptive transfer slows the growth of murine prostate and pancreatic ductal carcinoma |
title_sort |
nf-κb p50-deficient immature myeloid cell (p50-imc) adoptive transfer slows the growth of murine prostate and pancreatic ductal carcinoma |
publisher |
BMJ Publishing Group |
series |
Journal for ImmunoTherapy of Cancer |
issn |
2051-1426 |
publishDate |
2020-06-01 |
description |
BackgroundMacrophages and dendritic cells lacking the transcription factor nuclear factor kappa B p50 are skewed toward a proinflammatory phenotype, with increased cytokine expression and enhanced T cell activation; additionally, murine melanoma, fibrosarcoma, colon carcinoma, and glioblastoma grow slower in p50−/− mice. We therefore evaluated the efficacy of p50-negative immature myeloid cells (p50-IMCs) adoptively transferred into tumor-bearing hosts. Immature cells were used to maximize tumor localization, and pretreatment with 5-fluorouracil (5FU) was examined due to its potential to impair marrow production of myeloid cells, to target tumor myeloid cells and to release tumor neoantigens.MethodsWild-type (WT)-IMC or p50-IMC were generated by culturing lineage-negative marrow cells from WT or p50−/− mice in media containing thrombopoietin, stem cell factor and Flt3 ligand for 6 days followed by monocyte colony-stimulating factor for 1 day on ultralow attachment plates. Mice inoculated with Hi-Myc prostate cancer (PCa) cells or K-RasG12D pancreatic ductal carcinoma (PDC)-luciferase cells received 5FU followed 5 days later by three doses of 107 immature myeloid cells (IMC) every 3–4 days.ResultsPCa cells grew slower in p50−/− mice, and absence of host p50 prolonged the survival of mice inoculated orthotopically with PDC cells. IMC from Cytomegalovirus (CMV)-luciferase mice localized to tumor, nodes, spleen, marrow, and lung. 5FU followed by p50-IMC slowed PCa and PDC tumor growth, ~3-fold on average, in contrast to 5FU followed by WT-IMC, 5FU alone or p50-IMC alone. Slowed tumor growth was evident for 93% of PCa but only 53% of PDC tumors; we therefore focused on PCa for additional IMC analyses. In PCa, p50-IMC matured into F4/80+ macrophages, as well as CD11b+F4/80−CD11c+ conventional dendritic cells (cDCs). In both tumor and draining lymph nodes, p50-IMC generated more macrophages and cDCs than WT-IMC. Activated tumor CD8+ T cells were increased fivefold by p50-IMC compared with WT-IMC, and antibody-mediated CD8+ T cell depletion obviated slower tumor growth induced by 5FU followed by p50-IMC.Conclusions5FU followed by p50-IMC slows the growth of murine prostate and pancreatic carcinoma and depends on CD8+ T cell activation. Deletion of p50 in patient-derived marrow CD34+ cells and subsequent production of IMC for adoptive transfer may contribute to the therapy of these and additional cancers. |
url |
https://jitc.bmj.com/content/8/1/e000244.full |
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