Targeting monocyte differentiation for cancer immunotherapy

Dendritic cells (DCs) comprise a heterogeneous population of antigen-presenting cells that play a critical role in driving the adaptive immune response. We have recently reported that simultaneous inhibition of the metabolic sensors PPARγ and mTORC1 induces the differentiation of GM-CSF-treated human monocytes into highly immunogenic DCs. These DCs show a stronger phenotypic stability, superior immunogenicity, and a unique transcriptional profile, different from that of DCs obtained by conventional methods using GM-CSF and IL-4. Because infiltration of monocytes into peripheral tissues and their differentiation into macrophages or DCs are hallmarks of inflammation and cancer, our observations suggest that targeting monocyte differentiation may represent an attractive therapeutic strategy in cancer immunotherapy. This project has 3 objectives: (1) To perform a comprehensive functional characterization of human DCs induced by simultaneous inhibition of mTORC1 and PPARγ and test their therapeutic efficacy in the form of a DC vaccine in a humanized mouse tumor model. 2) To explore the underlying molecular events driving this differentiation process to identify novel regulators of monocyte cell fate commitment. 3) To evaluate in a humanized mouse tumor model wether the simultaneous inhibition of mTORC1 and PPARγ in vivo can induce the differentiation of tumor infiltrating monocytes into immunogenic DCs.