Abstract B68: NF-kB p50-deficient immature myeloid cell (p50-IMC) adoptive transfer slows the growth of murine prostate and pancreatic ductal carcinoma

Macrophages and dendritic cells lacking NF-kB p50 having an increased proinflammatory phenotype. Melanoma, fibrosarcoma, colon carcinoma, and glioblastoma grow slower in p50-/- mice, with tumor-associated macrophage M2-to-M1 reprogramming. We therefore evaluated the efficacy of NF-kB-deficient immature myeloid cell (p50-IMC) adoptive transfer. Immature myeloid cells (IMCs) were utilized to favor tumor and lymph node localization. WT-IMC or p50-IMC were generated by culturing lineage-negative marrow cells from WT or p50-/- mice in media containing TPO, SCF, and FL for six days followed by M-CSF for one day. Mice inoculated with Hi-Myc prostate cancer (PCa) or K-RasG12D pancreatic ductal carcinoma (PDC) transfected with luciferase received three doses of 1E7 IMCs every 3-4 days. IMC infusions were preceded by a single dose of 5-fluorouracil (5FU) to reduce marrow production of myeloid cells, to reduce tumor myeloid cell numbers, and to potentially release tumor neoantigens. PCa grew slower in p50-/- mice, and absence of host p50 led to prolonged survival of mice inoculated orthotopically with PDC. 5FU followed by p50-IMC slowed PCa or PDC tumor growth ~3-fold in contrast to 5FU followed by WT-IMC, 5FU alone, or p50-IMC alone. Slowed tumor growth was evident for 12 of 14 PCa tumors but only 8 of 15 PDC tumors, leading us to focus on PCa for additional analyses. p50-IMC predominantly generated PCa and draining lymph node F4/80+ macrophages, but also CD11b+F4/80-CD11c+ conventional dendritic cells, with tumor and nodal macrophages having increased Ly6C and MHCII and reduced MR compared to host macrophages, indicative of a proinflammatory phenotype. p50-IMC also led to 5-fold increased activated tumor CD8 T cells, and antibody-mediated CD8 T-cell depletion obviated slower tumor growth induced by 5FU followed by p50-IMC. Adoptive transfer of patient-derived NF-kB p50-deficient p50-IMC, potentially generated by expansion and gene editing of marrow CD34+ cells, may contribute to the therapy of these and additional cancers. Citation Format: Rahul R. Suresh, David J. Barakat, Theresa Barberi, Lei Zheng, Elizabeth M. Jaffee, Kenneth J. Pienta, Alan D. Friedman. NF-kB p50-deficient immature myeloid cell (p50-IMC) adoptive transfer slows the growth of murine prostate and pancreatic ductal carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B68.