NF-κB p50-deficient immature myeloid cell (p50-IMC) adoptive transfer slows the growth of murine prostate and pancreatic ductal carcinoma

Abstract

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-RasG12Dpancreatic ductal carcinoma (PDC)-luciferase cells received 5FU followed 5 days later by three doses of 107immature 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.

p50 suppresses cytotoxic T lymphocyte effector function to regulate tumor immune escape and response to immunotherapy

“…Although the function of and mechanism underlying NF-κB in tumor development have been largely focused on tumor cells, recent studies have started to shed light on the critical role of NF-κB in regulation of anti-tumor immunity. 7–16 36 Specifically, a recent CRISPR-based systemic immunotherapy target screening identified NF-κB as the strongest potential regulator of CTL effector function. 13 In this study, we extended p50 function to T-cell anti-tumor effector function and determined that p50 directly represses Gzmb expression in T cells to decrease Gzmb + CTLs in the tumor microenvironment.…”

“…It is well documented Open access that myeloid cell intrinsic NF-κB signaling promotes tumor initiation and progression. [7][8][9][10][11][12] NF-κB may directly and indirectly regulate T-cell activation, tumor infiltration and function. 7-10 13-16 However, polymorphisms in NFKB1 that diminish its expression have been linked to increased risk of colorectal cancer in humans.…”

“… 7–12 NF-κB may directly and indirectly regulate T-cell activation, tumor infiltration and function. 7–10 13–16 However, polymorphisms in NFKB1 that diminish its expression have been linked to increased risk of colorectal cancer in humans. 17 18 Furthermore, NF-κB1–deficient mice develop gastric cancer and this gastric cancer development requires loss of Nfkb1 in both epithelial and hematopoietic cells.…”

NF-κB in Cancer Immunity: Friend or Foe?

“…These complex functions of NF-κB could also be harnessed in a therapeutic perspective. Cell therapy using Ikbkb or Nfkb1 -deficient macrophages favors strong anti-tumor immunity and tumor rejection [ 27 , 35 ]. Conversely, as discussed in later sections, in vivo stimulation of TLRs using agonistic molecules, has a strong therapeutic potential in cancer, perhaps through its effect on macrophages [ 36 ].…”

Adoptive transfer of immature myeloid cells lacking NF‐κB p50 (p50‐IMC) impedes the growth of MHC‐matched high‐risk neuroblastoma

“…Melanoma, fibrosarcoma, colon cancer, glioblastoma, prostate cancer, and pancreatic ductal carcinoma each grow slower in syngeneic B6 p50 -/than in wild-type (WT) mice, with M2-to-M1 TAM reprogramming and increased tumor T cell activation evident in p50 -/tumor hosts [14][15][16][17]. In…”