期刊
ONCOIMMUNOLOGY
卷 5, 期 3, 页码 -出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/2162402X.2015.1091146
关键词
Apoptosis; fibroblasts; immunosuppression; MMP-13; PD1; PD-L1; PD-L2
资金
- INCa SIRIC (France)
- ARC Bendriss-Vermare, Fondation pour la Recherche Medicale (FRM, France) [4832]
- Ligue contre le Cancer (Comite de la Drome, France)
- LYRIC (LYon Recherche Integree en Cancerologie)
- LabEx (LABoratoire d'EXcellence) DEVweCAN Cancer, Developpement, therapies ciblees (Lyon, France)
- INCa PLBio (France) [2011-155, 2011-1-PL BIO-12-IC-1]
Whether fibroblasts regulate immune response is a crucial issue in the modulation of inflammatory responses. Herein, we demonstrate that foreskin fibroblasts (FFs) potently inhibit CD3(+) T cell proliferation through a mechanism involving early apoptosis of activated T cells. Using blocking antibodies, we demonstrate that the inhibition of T cell proliferation occurs through cell-to-cell interactions implicating PD-1 receptor expressed on T cells and its ligands, PD-L1 and PD-L2, on fibroblasts. Dual PD-1 ligand neutralization is required to abrogate (i) binding of the PD-1-Fc fusion protein, (ii) early apoptosis of T cells, and (iii) inhibition of T cell proliferation. Of utmost importance, we provide the first evidence that PD-1 ligand expression is regulated through proteolytic cleavage by endogenous matrix metalloproteinases (MMPs) without transcriptional alteration during culture-time. Using (i) different purified enzymatic activities, (ii) MMP-specific inhibitors, and (iii) recombinant human MMP-9 and MMP-13, we demonstrated that in contrast to CD80/CD86, PD-L1 was selectively cleaved by MMP-13, while PD-L2 was sensitive to broader MMP activities. Their cleavage by exogenous MMP-9 and MMP-13 with loss of PD-1 binding domain resulted in the reversion of apoptotic signals on mitogen-activated CD3(+) T cells. We suggest that MMP-dependent cleavage of PD-1 ligands on fibroblasts may limit their immunosuppressive capacity and thus contribute to the exacerbation of inflammation in tissues. In contrast, carcinoma-associated fibroblasts appear PD-1 ligand-depleted through MMP activity that may impair physical deletion of exhausted defective memory T cells through apoptosis and facilitate their regulatory functions. These observations should be considered when using the powerful PD-1/PD-L1 blocking immunotherapies.
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