Frontiers in Immunology (Aug 2022)

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

  • Giulia Monticone,
  • Zhi Huang,
  • Fred Csibi,
  • Silvana Leit,
  • David Ciccone,
  • Ameya S. Champhekar,
  • Jermaine E. Austin,
  • Deniz A. Ucar,
  • Fokhrul Hossain,
  • Salome V. Ibba,
  • A. Hamid Boulares,
  • Nicholas Carpino,
  • Keli Xu,
  • Samarpan Majumder,
  • Barbara A. Osborne,
  • Christine Loh,
  • Lucio Miele

DOI
https://doi.org/10.3389/fimmu.2022.987298
Journal volume & issue
Vol. 13

Abstract

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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.

Keywords