Tumors employ a number of mechanisms to promote immune escape, including the infiltration of different immunosuppressive cells in the tumor microenvironment such as T-regulatory cells (Treg). However, the specific signals within tumor cells that regulate the recruitment of Tregs, giving rise to tumor-induced immunosuppression, remain elusive. Based on our new preliminary data, we hypothesize that WEE1, an important regulator for cell cycle checkpoints, maintains an immunosuppressive and pro- tumorigenic microenvironment, and suppressing WEE1 activity, including via a clinically relevant WEE1 inhibitor, may be therapeutically beneficial by boosting immune-mediated tumor clearance. This proposal seeks to characterize the novel regulatory perspectives of WEE1-mediated crosstalk between tumor cells and host immune cells that should significantly forward the field. Specifically, this project is searching for the molecular mechanisms of WEE1-mediated Treg regulation and development of new effective combinatorial strategies. Our work will thus identify an unappreciated role of WEE1 inhibition in reversing tumor-induced immune suppression.
WEE1 appears to be a key regulator to finely control functional Treg differentiation and expansion. Our work will thus not only advance current understandings of how Treg differentiation and expansion are regulated during tumor development, but also provide new insights into the molecular basis of designing WEE1-targeted cancer immunotherapies.
| Long, Alan; Dominguez, Donye; Qin, Lei et al. (2018) Type 2 Innate Lymphoid Cells Impede IL-33-Mediated Tumor Suppression. J Immunol 201:3456-3464 |
