Regulation of Tuft Cells in Innate Immunity and Cancer

Tuft cells are epithelial cells that monitor the environment for presence of microorganisms in several organs, and activate innate immunity upon detection of pathogens. In the context of tumorigenesis, they have functions to either promote or suppress cancer development and progression. Their role in cancers is dependent on the activation of different downstream effector pathways. In this thesis, I explored regulation of tuft cell function in the model of intestinal activation of type 2 immunity, and the role of tuft cells in prostate cancer. We show that the effector function of tuft cells is differentially regulated between sexes through the role of Protein Tyrosine Kinase 6 (PTK6). In male mice, PTK6 regulates Il25 and Irag2 that are required for the activation of innate lymphoid cells type 2, cells which are the main signaling hub in orchestrating the innate type 2 immunity response. Consequently, male mice that lack Ptk6 do not have expansion of secretory cell types, tuft and goblet cells. On the other hand, PTK6 is not required in female mice to regulate this response. Furthermore, females show stronger activation of type 2 immunity activation in the intestine. In the second part of this thesis, I show that tuft cells are upregulated with prostate cancer development and progression. PTK6 is not required for expansion of tuft cells in prostate cancer. Using bioinformatic analysis, we propose that in prostate cancer tuft cells promote tumorigenesis through expression of IL-25 and other factors involved in regulating immunosuppression, angiogenesis, cancer cell migration and epithelial-mesenchymal transition.