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Oncotarget. 2017 Jun 27;8(26):41841-41853. doi: 10.18632/oncotarget.18360.

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

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


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.


Cbl-b; T cells; cancer immunotherapy; immune checkpoints

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