The premetastatic niche represents a specialized environment educated to be receptive to disseminated tumor cells by secreted factors from the primary tumor. Prior to the arrival of the first cancer cells, circulating bone marrow progenitors are known to home to lungs, where they differentiate into a suppressive cell population, instructing a prometastatic environment. Kaplan and colleagues now exploit this homing capacity and use genetically engineered myeloid cells (GEMys) as a platform for delivering cytokines into the premetastatic niche (Cell 184, 2033–2052; 2021).
First, the authors extensively profiled the premetastatic lung by flow cytometry and single-cell RNA sequencing and identified a profoundly remodeled immune microenvironment characterized by increased myeloid cells and a marked reduction in T cells. To reshape this immunosuppressive environment, they generated GEMys to deliver IL-12, a cytokine with potent antitumor activity, by infecting hematopoietic stem cells with an IL-12-encoding lentivirus. The resulting heterogeneous population of myeloid cells strongly elevated IL-12 in mouse lungs shortly after intravenous administration and reshaped the premetastatic environment, with an accumulation of T cells, natural killer cells and dendritic cells. Next, the authors used a rhabdomyosarcoma model of spontaneous lung metastasis to assess whether the reprogrammed lung environment would affect the metastatic cascade. Notably, lung metastasis was profoundly reduced after the administration of GEMys, an effect that was also recapitulated in a pancreatic cancer liver-metastasis model. The efficacy of IL-12-delivering GEMys was dependent on CD8+ T cells and induced long-term memory formation. Further showcasing the therapeutic implications, the authors demonstrated efficacy of GEMys in combination with chemotherapy and adoptive T cell transfer in mouse models. Finally, they engineered human monocytes to express IL-12 and showed that in co-culture with T cells, these were capable of promoting production of the cytokine IFN-γ by the T cell compartment.
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