| Autor: |
Apoorvi, Chaudhri, Yanping, Xiao, Alyssa N, Klee, Xiaoxu, Wang, Baogong, Zhu, Gordon J, Freeman |
| Rok vydání: |
2017 |
| Předmět: |
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| Zdroj: |
Cancer Immunol Res |
| ISSN: |
2326-6074 |
| Popis: |
Programmed death ligand 1 (PD-L1)–mediated immune suppression regulates peripheral tolerance and is often co-opted by tumors to evade immune attack. PD-L1 binds to PD-1 but also binds to B7–1 (CD80) to regulate T-cell function. The binding interaction of PD-L1 with B7–1 and its functional role need further investigation to understand differences between PD-1 and PD-L1 tumor immunotherapy. We examined the molecular orientation of PD-L1 binding to B7–1 using cell-to-cell binding assays, ELISA, and flow cytometry. As expected, PD-L1 transfected cells bound to PD-1 transfected cells and B7–1 cells bound to CD28 or CTLA-4 transfected cells; however, PD-L1 cells did not bind to B7–1 cells. By ELISA and flow cytometry with purified proteins, we found PD-L1 and B7–1 had a strong binding interaction only when PD-L1 was flexible. Soluble PD-1 and B7–1 competed for binding to PD-L1. Binding of native PD-L1 and B7–1 in cis on the same cell surface was demonstrated with NanoBiT proximity assays. Thus, PD-L1–B7–1 interaction can occur in cis on the same cell but not in trans between two cells, which suggests a model in which PD-L1 can bend via its 11-amino acid, flexible stalk to bind to B7–1 in cis, in a manner that can competitively block the binding of PD-L1 to PD-1 or of B7–1 to CD28. This binding orientation emphasizes the functional importance of coexpression of PD-L1 and B7–1 on the same cell. We found such coexpression on tumor-infiltrating myeloid cells. Our findings may help better utilize these pathways in cancer immunotherapy. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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