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

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.

Publisher

Frontiers Media SA

Subject

Immunology,Immunology and Allergy

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