Priority Research Papers:

Cblb-deficient T cells are less susceptible to PD-L1-mediated inhibition

Sebastian Peer, Gottfried Baier and Thomas Gruber _

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Oncotarget. 2017; 8:41841-41853. https://doi.org/10.18632/oncotarget.18360

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Sebastian Peer1, Gottfried Baier1 and Thomas Gruber1

1 Department for Medical Genetics, Molecular and Clinical Pharmacology, Division of Translational Cell Genetics, Medical University of Innsbruck, Innsbruck, Austria

Correspondence to:

Thomas Gruber, email:

Keywords: immune checkpoints, cancer immunotherapy, T cells, Cbl-b

Received: November 30, 2016 Accepted: May 22, 2017 Published: June 03, 2017


Modulation of the immune system for the treatment of primary and metastatic tumors has been a goal of cancer research for many years. The E3 ubiquitin ligase Cbl-b has been established as an intracellular checkpoint that limits T cell activation, critically contributing to the maintenance of self-tolerance. Furthermore, it has been shown that Cblb deficiency enhances T cell effector functions towards tumors. Blockade of the immune checkpoints CTLA-4 and PD-1/PD-L1 has recently emerged as a promising strategy in the development of effective cancer immune therapies. Therefore, we explored the concept of targeting different checkpoints concomitantly. Interestingly, we observed that CTLA-4 but not PD-L1 based immunotherapy selectively enhanced the anti-tumor phenotype of Cblb-deficient mice. In agreement with the in vivo results, in vitro experiments showed that Cblb-/- T cells were less susceptible to PD-L1-mediated suppression of T cell proliferation and IFNγ secretion. Taken together, our findings reveal a so far unappreciated function of Cbl-b in the regulation of PD-1 signaling in murine T cells.

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