Targeting Cbl-b in cancer immunotherapy

Abstract

Cancer immunotherapy with immune-checkpoint blockade has improved the outcomes of patients with various malignancies, yet a majority do not benefit or develop resistance. To address this unmet need, efforts across the field are targeting additional coinhibitory receptors, costimulatory proteins, and intracellular mediators that could prevent or bypass anti-PD1 resistance mechanisms. The CD28 costimulatory pathway is necessary for antigen-specific T cell activation, though prior CD28 agonists did not translate successfully to clinic due to toxicity. Casitas B lymphoma-b (Cbl-b) is a downstream, master regulator of both CD28 and CTLA-4 signaling. This E3 ubiquitin ligase regulates both innate and adaptive immune cells, ultimately promoting an immunosuppressive tumor microenvironment (TME) in the absence of CD28 costimulation. Recent advances in pharmaceutical screening and computational biology have enabled the development of novel platforms to target this once ‘undruggable’ protein. These platforms include DNA encoded library screening, allosteric drug targeting, small-interfering RNA inhibition, CRISPR genome editing, and adoptive cell therapy. Both genetic knock-out models and Cbl-b inhibitors have been shown to reverse immunosuppression in the TME, stimulate cytotoxic T cell activity, and promote tumor regression, findings augmented with PD1 blockade in experimental models. In translating Cbl-b inhibitors to clinic, we propose specific gene expression profiles that may identify patient populations most likely to benefit. Overall, novel Cbl-b inhibitors provide antigen-specific immune stimulation and are a promising therapeutic tool in the field of immuno-oncology.

GABA induced by sleep deprivation promotes the proliferation and migration of colon tumors through miR-223-3p endogenous pathway and exosome pathway

“…Following, we verified the function of CBLB in colon cancer. CBLB is a proto-oncogene considered as a new target for tumor immunotherapy [ 41 ]. However, its expression in colon cancer has not yet been reported.…”

Biologically Interpretable Deep Learning To Predict Response to Immunotherapy In Advanced Melanoma Using Mutations and Copy Number Variations

“…As a upstream gene, the HRAS which enriched in ErbB signaling pathway and JAK-STAT signaling pathway could affect on the effectiveness of immunotherapy through regulating PI3K signaling 30. Meanwhile, the gene CBLB enriched in T cell receptor signaling pathway and ErbB signaling pathway could inhibit T cell transcriptional activity and promote immune tolerance31 and had been shown to act as an intracellular checkpoint,32 Augustin et al reported that CBLB as a key downstream mediator of PD-1 and CTLA-4 signaling pathway could influence the resistant to immunotherapy 33. Gu et al found that the gene TRAF3 enriched in pathways in cancer was a suppressor of NF- κ B pathway and associated with better survival in ICIs-naïve cancer patients and better ICIs response 34.…”

Rising Star in Immunotherapy: Development and Therapeutic Potential of Small-Molecule Inhibitors Targeting Casitas B Cell Lymphoma-b (Cbl-b)

“…ICIs play a crucial role in regulating the expression of Cbl-b. The costimulatory molecule CD28 promotes ubiquitination and degradation of Cbl-b, while the coinhibitory molecule CTLA-4 can induce Cbl-b expression after interaction with B7, thereby modulating various signaling pathways and amplifying T-cell activation, such as cytokine or TCR-mediated signal transduction. , In addition, the expression of Cbl-b also limits the production of IL-2 and inhibits the mitogen-activated protein kinase (MAPK)/extracellular regulated protein kinases (ERK) mediated signal transduction downstream of the IL-2 receptor, thus reducing T cells proliferation. , …”