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 

TITLE=Targeting the Cbl-b-Notch1 axis as a novel immunotherapeutic strategy to boost CD8+ T-cell responses

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.987298

DOI=10.3389/fimmu.2022.987298

ISSN=1664-3224

ABSTRACT=<p>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.</p>