B7-H1 antibodies lose antitumor activity due to activation of p38 MAPK that leads to apoptosis of tumor-reactive CD8+ T cells

B7-H1 (aka PD-L1) blocking antibodies have been used in treatment of human cancers through blocking B7-H1 expressed by tumor cells; however, their impact on B7-H1 expressing tumor-reactive CD8 + T cells is still unknown. Here, we report that tumor-reactive CD8 + T cells expressing B7-H1 are function...

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Bibliographic Details
Published in:Scientific reports 2016-11, Vol.6 (1), p.36722-36722, Article 36722
Main Authors: Liu, Xin, Wu, Xiaosheng, Cao, Siyu, Harrington, Susan M., Yin, Peng, Mansfield, Aaron S., Dong, Haidong
Format: Article
Language:English
Subjects:
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Antibodies
Antitumor activity
Apoptosis
B7 antigen
Cancer
Cancer immunotherapy
CD8 antigen
Cell activation
Cell survival
Cytoplasm
Deoxyribonucleic acid
DNA
DNA-dependent protein kinase
Effector cells
Humanities and Social Sciences
Immunoglobulins
Immunotherapy
Lymphocytes
Lymphocytes T
MAP kinase
multidisciplinary
PD-L1 protein
Protein kinase C
Science
Tumor cells
Tumors
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Summary:B7-H1 (aka PD-L1) blocking antibodies have been used in treatment of human cancers through blocking B7-H1 expressed by tumor cells; however, their impact on B7-H1 expressing tumor-reactive CD8 + T cells is still unknown. Here, we report that tumor-reactive CD8 + T cells expressing B7-H1 are functional effector cells. In contrast to normal B7-H1 blocking antibody, B7-H1 antibodies capable of activating p38 MAPK lose their antitumor activity by deleting B7-H1 + tumor-reactive CD8 + T cells via p38 MAPK pathway. B7-H1 deficiency or engagement with certain antibody results in more activation of p38 MAPK that leads to T cell apoptosis. DNA-PKcs is a new intracellular partner of B7-H1 in the cytoplasm of activated CD8 + T cells. B7-H1 suppresses p38 MAPK activation by sequestering DNA-PKcs in order to preserve T cell survival. Our findings provide a new mechanism of action of B7-H1 in T cells and have clinical implications in cancer immunotherapy when anti-B7-H1 (PD-L1) antibody is applied.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep36722