c-Cbl targets PD-1 in immune cells for proteasomal degradation and modulates colorectal tumor growth
| العنوان: | c-Cbl targets PD-1 in immune cells for proteasomal degradation and modulates colorectal tumor growth |
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| المؤلفون: | Jean M. Francis, Razie Amraei, Elias Zavaro, Nader Rahimi, Marc A Napoleon, Jonathan D. Ravid, Uma R. Phatak, Nkiruka Arinze, Vipul C. Chitalia, Wenqing Yin, Chimera Lyle, Joshua Walker, Irva Vellard, Ian R. Rifkin, Sean Richards, Mostafa Belghasem, Kei Yasuda |
| المصدر: | Scientific Reports Scientific Reports, Vol 9, Iss 1, Pp 1-14 (2019) |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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. |
| تدمد: | 2045-2322 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d3ad9517985da2f5ac095da041d402db https://pubmed.ncbi.nlm.nih.gov/31882749 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....d3ad9517985da2f5ac095da041d402db |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20452322 |
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