Casitas B-lineage lymphoma-b (Cbl-b) is an E3 ubiquitin ligase that negatively regulates T cell activation. Cbl-b(-/-) T cells are hyper-reactive and co-stimulation independent, and Cbl-b(-/-) mice demonstrate robust T cell and NK cell-mediated antitumor immunity. As a result of these murine studies, Cbl-b is considered a potential target for therapeutic manipulation in human cancer immunotherapy. The PD-L1/PD-1 pathway of immune regulation is presently an important therapeutic focus in tumor immunotherapy, and although Cbl-b(-/-) mice have been shown to be resistant to several immuno-regulatory mechanisms, the sensitivity of Cbl-b(-/-) mice to PD-L1-mediated suppression has not been reported. We now document that Cbl-b(-/-) T cells and NK cells are resistant to PD-L1/PD-1-mediated suppression. Using a PD-L1 fusion protein (PD-L1 Ig), this resistance is shown for both in vitro proliferative responses and IFN-γ production and is not associated with decreased PD-1 expression on Cbl-b(-/-) cells. In coculture studies, Cbl-b(-/-) CD8(+), but not CD4(+) T cells, diminish the PD-L1 Ig-mediated suppression of bystander naïve WT CD8(+) T cells. Using an in vivo model of B16 melanoma in which numerous liver metastases develop in WT mice in a PD-1 dependent manner, Cbl-b(-/-) mice develop significantly fewer liver metastases without the administration of anti-PD-1 antibody. Overall, our findings identify a new mode of immuno-regulatory resistance associated with Cbl-b deficiency and suggest that resistance to PD-L1/PD-1-mediated suppression is a novel mechanism by which Cbl-b deficiency leads to enhanced antitumor immunity. Our results suggest that targeting Cbl-b in cancer immunotherapy offers the opportunity to simultaneously override numerous relevant "checkpoints," including sensitivity to regulatory T cells, suppression by TGF-β, and immune regulation by both CTLA-4 and, as we now report, by the PD-L1/PD-1 pathway.
Pharmacology, Toxicology and Pharmaceutical Science
3
4%
Other
8
11%
Unknown
14
20%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 2. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 30 January 2017.
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#16,722,913
of 25,377,790 outputs
Outputs from Frontiers in immunology
#18,330
of 31,531 outputs
Outputs of similar age
#255,439
of 422,426 outputs
Outputs of similar age from Frontiers in immunology
#252
of 372 outputs
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