Transcriptional Modulation of Tumor-Associated Macrophages to Facilitate Prostate Cancer Immunotherapy
Technical Report,01 Sep 2016,31 Aug 2017
Johns Hopkins University Baltimore United States
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Prostate cancer PCa contains abundant tumor-associated macrophages TAMs, with increased TAM M2 polarization correlating with disease stage, emergence of castration-resistance, and worse prognosis. We hypothesize that targeting TAM transcription factors that mediate their M2 polarization, reprogramming them into the pro-inflammatory M1 state, will provide a novel approach to PCa therapy, and we seek to assess whether adoptive transfer monocytes lacking a key TAM transcription factor shows therapeutic utility, alone or with checkpoint inhibition. During the current reporting year we found that a murine PCa line grows slower in mice lacking NF-kB p50 compared with wild-type controls and in KLF4ffLys-Cre mice vs KLF4ff controls, with increased TAM M1 polarization, particularly in p50-- hosts, and with increased number and activation of tumor T cells, predominantly CD4 T cells in p50-- vs wild-type and CD8 T cells in KLF4ffLys-Cre vs KLF4ff tumor recipients. We also demonstrated that expansion of marrow progenitors in SCFFLTPO for 6 days, culture in M-CSF for 1 day, and adoptive transfer allows PCa tumor localization in preference to normal organs. And we find that anti-PD-1 is active in our tumor model. Thus, we have identified two transcription factors whose down-regulation in PCa TAMs contributes to tumor control and have begun to optimize a novel immunotherapy including adoptive transfer of gene modified myeloid cells.
- Medicine and Medical Research