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.
Highlights
B7-H1 blocking antibodies have been used in treatment of human cancers through blocking B7-H1 expressed by tumor cells; their impact on B7-H1 expressing tumor-reactive CD8+ T cells is still unknown
Since B7-H1 expression on tumor-infiltrating lymphocytes (TILs) has a predictive value in anti-B7-H1 therapy response[5,6], we first examined the expression kinetics of B7-H1 on TTR cells within growing tumors
Using PD-1+CD11ahigh expression as a surrogate marker to define TTR cells[10,11], we found that the number of TTR cells gradually increased and peaked around day 15 after tumor seeding in mice (Fig. 1A)
Summary
B7-H1 expression identifies effector CTLs within tumor tissues. Since B7-H1 expression on TILs has a predictive value in anti-B7-H1 therapy response[5,6], we first examined the expression kinetics of B7-H1 on TTR cells within growing tumors. It is not clear why NU7026 did not suppress p38 MAPK activation in activated CD8+ T cells treated with control IgG. Our results caution that some B7-H1 blocking mAbs may lose their in vivo antitumor activity by inducing T cell apoptosis through p38 MAPK activation To avoid this scenario in cancer treatment with anti-B7-H1 antibody, B7-H1 blocking antibodies should be tested for their potential capability in activation of p38 MAPK or induction of apoptosis in activated CD8+ T cells. 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
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