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

Xin Liu, Xiaosheng Wu, Siyu Cao, Susan M. Harrington, Peng Yin, Aaron Mansfield, Haidong M Dong

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Article number36722
JournalScientific Reports
Volume6
DOIs
StatePublished - Nov 8 2016

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p38 Mitogen-Activated Protein Kinases
Apoptosis
T-Lymphocytes
Antibodies
Neoplasms
Blocking Antibodies
DNA
Immunotherapy
Cell Survival
Cytoplasm

ASJC Scopus subject areas

  • General

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B7-H1 antibodies lose antitumor activity due to activation of p38 MAPK that leads to apoptosis of tumor-reactive CD8+T cells. / Liu, Xin; Wu, Xiaosheng; Cao, Siyu; Harrington, Susan M.; Yin, Peng; Mansfield, Aaron; Dong, Haidong M.

In: Scientific Reports, Vol. 6, 36722, 08.11.2016.

Research output: Contribution to journalArticle

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AU - Yin, Peng

AU - Mansfield, Aaron

AU - Dong, Haidong M

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