DUSP11 is an intracellular innate immune checkpoint in lung adenocarcinoma

Abstract

The discovery of immune checkpoints and the rapid growth of immuno-oncology (IO) have sparked tremendous efforts to utilize the immune system to treat a wide range of cancer types/subtypes. While the major focus of IO over the past decades has been to manipulate the adaptive immune system, recent attention has been given to manipulating the innate immune system to treat cancer and/or to enhance adaptive responses. In this work we detail the intracellular protein, Dual Specificity Phosphatase 11 (DUSP11), as an innate immune checkpoint (iIC) in Non-Small Cell Lung Cancer (NSCLC) adenocarcinoma (LUAD). Expression of this atypical phosphatase is correlated with patient survival for multiple cancer types, and we show here that its activity is important for the viability of lung cancer cells in vitro. Specifically, we demonstrate that DUSP11 knockdown in LUAD cells induces apoptosis and an innate immune response capable of activating other cells in vitro, and we provide evidence that these phenotypes are primarily mediated by the pattern recognition receptor, retinoic acid inducible gene I (RIG-I). Finally, we show that expression of DUSP11 is important for tumor engraftment and growth of human LUAD in mice. Overall, these data are the first to establish DUSP11 as an immunosuppressive, pro-neoplastic, and potentially targetable protein in LUAD. In addition, our data suggests that the anti-cancer mechanisms induced by diminishing the activity of DUSP11 are likely to be generalizable to other cancer types such as breast cancer, warranting future investigation and therapeutic development.