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

Year: 2022
Type: article
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.
DOI: 10.3389/fimmu.2022.987298
Authors: Giulia Monticone, Fred Csibi, Silvana Leit, David Ciccone, Ameya S. Champhekar, Jermaine E. Austin, Deniz A. Ucar, Fokhrul Hossain, Zhi Huang, Salome V. Ibba, A. Hamid Boulares, Nicholas Carpino, Samarpan Majumder, Keli Xu, Barbara A. Osborne, Christine Loh, Lucio Miele
Institutions: Louisiana State University, Louisiana State University Health Sciences Center New Orleans, University of California, Los Angeles, University of Virginia, Stony Brook University, University of Mississippi Medical Center, University of Massachusetts Amherst
Language: English
Subfield: Oncology
Field: Medicine
Open Access status: gold
Estimated APC paid: $2,950
OpenAlex ID: W4293194777
FWCI: 0.903
Cites: 61
Cited by: 12
Related to: 10