While previous ex vivo studies have only shown PD-L1 and CD80 binding in cis on APCs, Zhang et al. observed direct binding in trans between PD-L1 on T cells and CD80 on tumor cells in vivo. 43H12 Ab, which blocks PD-L1 binding to CD80, but not to PD-1, enhanced expansion of IFNγ-producing CD8+ TEM cells and IFNγ-dependent NOS2+ TAMs, which produce NO and inhibit tumor growth. While blocking cis PD-L1/CD80 interactions has previously been shown to dampen antitumor immunity, blocking just trans interactions or both trans and cis interactions enhanced antitumor immunity, which was dependent on tumor expression of MHC-I and T cell expression of CD28.
Contributed by Lauren Hitchings
ABSTRACT: PD-L1 has two receptors: PD-1 and CD80. Previous reports assumed that PD-L1 and CD80 interacted in trans, but recent reports showed that only cis PD-L1/CD80 interactions existed, and prevention of cis PD-L1/CD80 interactions on antigen-presenting cells (APCs) reduced antitumor immunity via augmenting PD-L1/PD-1 and CD80/CTLA4 interactions between T and APCs. Here, using tumor-bearing mice capable of cis and trans or trans only PD-L1/CD80 interactions, we show that trans PD-L1/CD80 interactions do exist between tumor and T cells, and the effects of trans PD-L1/CD80 interactions require tumor cell expression of MHC-I and T cell expression of CD28. The blockade of PD-L1/CD80 interactions in mice with both cis and trans interactions or with only trans interactions augments antitumor immunity by expanding IFN-_-producing CD8(+) T cells and IFN-_-dependent NOS2-expressing tumor-associated macrophages. Our studies indicate that although cis and trans PD-L1/CD80 interactions may have opposite effects on antitumor immunity, the net effect of blocking PD-L1/CD80 interactions in vivo augments CD8(+) T cell-mediated antitumor immunity.
Author Info: (1) Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope Medical Ce
Author Info: (1) Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope Medical Center, Duarte, CA 91010. Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA 91010. (2) Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope Medical Center, Duarte, CA 91010. Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA 91010. Fujian Medical University Center of Translational Hematology, Fujian Institute of Hematology, and Fujian Medical University Union Hospital, Fuzhou 350001, China. (3) Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope Medical Center, Duarte, CA 91010. Irell & Manella Graduate School of Biological Sciences, City of Hope National Medical Center, Duarte, CA 91010. (4) Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope Medical Center, Duarte, CA 91010. Irell & Manella Graduate School of Biological Sciences, City of Hope National Medical Center, Duarte, CA 91010. (5) Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390. (6) Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope Medical Center, Duarte, CA 91010. Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA 91010. (7) Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope Medical Center, Duarte, CA 91010. Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA 91010. Fujian Medical University Center of Translational Hematology, Fujian Institute of Hematology, and Fujian Medical University Union Hospital, Fuzhou 350001, China. (8) Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope Medical Center, Duarte, CA 91010. (9) Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390. (10) Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope Medical Center, Duarte, CA 91010. (11) Fred Hutchinson Cancer Center, Seattle, WA 98109. (12) Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. (13) Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope Medical Center, Duarte, CA 91010. Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA 91010.
