PD-1 mediates paralysis of ovarian cancer-infiltrating dendritic cells through SHP-2 dependent and independent NFkB inactivation (TUM3P.1048)
| Autor: | Lavakumar Karyampudi, Purushottam Lamichhane, James krempski, Kimberly Kalli, Marshall Behrens, Doris Vargas, Lynn Hartmann, Jo Marie Janco, Karen Hedin, Allan Dietz, Ellen Goode, Keith Knutson |
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| Rok vydání: | 2015 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 194:70.5-70.5 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | The PD-1:PD-L1 axis is a major immune regulatory pathway that blunts T cell activation in the tumor microenvironment. We recently identified that PD-1 is also upregulated on ovarian mouse tumor-infiltrating myeloid dendritic cells (TIDCs) that exhibit an immune suppressive phenotype. Extending those observations in this study, we now report that PD-1 is also expressed on human myeloid TIDCs of ovarian cancer patients, on which it suppresses the expression of co-stimulatory molecules (CD40 and CD80) as well as production of inflammatory cytokines. Mechanistic studies revealed that PD-1 on TIDCs is associated with Src homology domain-containing phosphatase-2 (SHP-2) and that PD-1-mediated blockade of NFkB-dependent cytokine release is SHP-2 dependent. PD-1 also inhibits NFkB-mediated antigen presentation which appears, however, to be independent of SHP-2. Thus, suppression of NFkB is critical in mediating PD-1-induced paralysis of ovarian tumor-associated immune TIDCs and is mediated through multiple signaling circuits that are both SHP-2 dependent and independent. |
| Databáze: | OpenAIRE |
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