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c-Cbl targets PD-1 in immune cells for proteasomal degradation and modulates colorectal tumor growth
- Source :
- Scientific Reports, Scientific Reports, Vol 9, Iss 1, Pp 1-14 (2019)
- Publication Year :
- 2019
-
Abstract
- Casitas B lymphoma (c-Cbl) is an E3 ubiquitin ligase and a negative regulator of colorectal cancer (CRC). Despite its high expression in immune cells, the effect of c-Cbl on the tumor microenvironment remains poorly understood. Here we demonstrate that c-Cbl alters the tumor microenvironment and suppresses Programmed cell death-1 (PD-1) protein, an immune checkpoint receptor. Using syngeneic CRC xenografts, we observed significantly higher growth of xenografts and infiltrating immune cells in c-Cbl+/− compared to c-Cbl+/+ mice. Tumor-associated CD8+ T-lymphocytes and macrophages of c-Cbl+/− mice showed 2–3-fold higher levels of PD-1. Functionally, macrophages from c-Cbl+/− mice showed a 4–5-fold reduction in tumor phagocytosis, which was restored with an anti-PD-1 neutralizing antibody suggesting regulation of PD-1 by c-Cbl. Further mechanistic probing revealed that C-terminus of c-Cbl interacted with the cytoplasmic tail of PD-1. c-Cbl destabilized PD-1 through ubiquitination- proteasomal degradation depending on c-Cbl’s RING finger function. This data demonstrates c-Cbl as an E3 ligase of PD-1 and a regulator of tumor microenvironment, both of which were unrecognized components of its tumor suppressive activity. Advancing immune checkpoint and c-Cbl biology, our study prompts for probing of PD-1 regulation by c-Cbl in conditions driven by immune checkpoint abnormalities such as cancers and autoimmune diseases.
- Subjects :
- Proteasome Endopeptidase Complex
Ubiquitin-Protein Ligases
Cell
Programmed Cell Death 1 Receptor
lcsh:Medicine
CD8-Positive T-Lymphocytes
Article
03 medical and health sciences
0302 clinical medicine
Immune system
Ubiquitin
hemic and lymphatic diseases
medicine
Tumor Microenvironment
Animals
Humans
Proto-Oncogene Proteins c-cbl
Phosphorylation
lcsh:Science
Receptor
Cancer models
030304 developmental biology
Mice, Knockout
0303 health sciences
Tumor microenvironment
Multidisciplinary
biology
Chemistry
Macrophages
lcsh:R
fungi
Ubiquitination
Immune checkpoint
Ubiquitin ligase
Tumor Burden
Colon cancer
Gene Expression Regulation, Neoplastic
enzymes and coenzymes (carbohydrates)
medicine.anatomical_structure
030220 oncology & carcinogenesis
biology.protein
Cancer research
lcsh:Q
biological phenomena, cell phenomena, and immunity
Colorectal Neoplasms
CD8
hormones, hormone substitutes, and hormone antagonists
Subjects
Details
- ISSN :
- 20452322
- Volume :
- 9
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Scientific reports
- Accession number :
- edsair.doi.dedup.....d3ad9517985da2f5ac095da041d402db