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 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.
Department of Urology, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
Xin
X
Liu
Division of Hematology, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
Xiaosheng
X
Wu
Department of Urology, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
Siyu
S
Cao
Department of Urology, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
Susan M
SM
Harrington
Department of Urology, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
Peng
P
Yin
Division of Medical Oncology, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
Aaron S
AS
Mansfield
Department of Urology, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.|Department of Immunology, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
Haidong
H
Dong
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D060890:B7-H1 Antigen / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D003593:Cytoplasm / Q000378:metabolism; D004789:Enzyme Activation; D017353:Gene Deletion; D007167:Immunotherapy; D008213:Lymphocyte Activation; D020935:MAP Kinase Signaling System; D008546:Melanoma, Experimental; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases