Author:
Monticone Giulia,Huang Zhi,Csibi Fred,Leit Silvana,Ciccone David,Champhekar Ameya S.,Austin Jermaine E.,Ucar Deniz A.,Hossain Fokhrul,Ibba Salome V.,Boulares A. Hamid,Carpino Nicholas,Xu Keli,Majumder Samarpan,Osborne Barbara A.,Loh Christine,Miele Lucio
Abstract
A critical feature of cancer is the ability to induce immunosuppression and evade immune responses. Tumor-induced immunosuppression diminishes the effectiveness of endogenous immune responses and decreases the efficacy of cancer immunotherapy. In this study, we describe a new immunosuppressive pathway in which adenosine promotes Casitas B-lineage lymphoma b (Cbl-b)-mediated Notch1 degradation, causing suppression of CD8+ T-cells effector functions. Genetic knockout and pharmacological inhibition of Cbl-b prevents Notch1 degradation in response to adenosine and reactivates its signaling. Reactivation of Notch1 results in enhanced CD8+ T-cell effector functions, anti-cancer response and resistance to immunosuppression. Our work provides evidence that targeting the Cbl-b-Notch1 axis is a novel promising strategy for cancer immunotherapy.
Subject
Immunology,Immunology and Allergy
Cited by
6 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献