Li Jian-Ming, Petersen Christopher T, Li Jing-Xia, Panjwani Reema, Chandra Daniel J, Giver Cynthia R, Blazar Bruce R, Waller Edmund K
Department of Hematology/Oncology, Emory University, Atlanta, Georgia.
Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, China.
Cancer Res. 2016 Dec 1;76(23):6802-6815. doi: 10.1158/0008-5472.CAN-16-0427. Epub 2016 Sep 26.
The goal of allogeneic bone marrow transplantation (allo-BMT) is elimination of leukemia cells through the graft-versus-leukemia (GvL) activity of donor cells, while limiting graft-versus-host disease (GvHD). Immune checkpoint pathways regulate GvL and GvHD activities, but blocking antibodies or genetic inactivation of these pathways can cause lethal GVHD. Vasoactive intestinal peptide (VIP) is an immunosuppressive neuropeptide that regulates coinhibitory pathways; its role in allo-BMT has not been studied. We found VIP transiently expressed in donor NK, NK-T, dendritic cells, and T cells after allo transplant, as well as host leukocytes. A peptide antagonist of VIP signaling (VIPhyb) increased T-cell proliferation in vitro and reduced IL10 expression in donor T cells. Treatment of allo-BMT recipients with VIPhyb, or transplanting donor grafts lacking VIP (VIP-KO), activated donor T-cells in lymphoid organs, reduced T-cell homing to GvHD target organs, and enhanced GvL without increasing GvHD in multiple allo-BMT models. Genetic or ex vivo depletion of donor NK cells or CD8 T cells from allografts abrogated the VIPhyb-enhanced GvL activity. VIPhyb treatment led to downregulation of PD-1 and PD-L1 expression on donor immune cells, increased effector molecule expression, and expanded oligoclonal CD8 T cells that protected secondary allo transplant recipients from leukemia. Blocking VIP signaling thus represents a novel pharmacologic approach to separate GvL from GvHD and enhance adaptive T-cell responses to leukemia-associated antigens in allo-BMT. Cancer Res; 76(23); 6802-15. ©2016 AACR.
异基因骨髓移植（allo - BMT）的目标是通过供体细胞的移植物抗白血病（GvL）活性消除白血病细胞，同时限制移植物抗宿主病（GvHD）。免疫检查点通路调节GvL和GvHD活性，但阻断抗体或这些通路的基因失活可导致致命的移植物抗宿主病。血管活性肠肽（VIP）是一种调节共抑制通路的免疫抑制神经肽；其在allo - BMT中的作用尚未得到研究。我们发现，在allo移植后，VIP在供体自然杀伤细胞（NK）、NK - T细胞、树突状细胞和T细胞以及宿主白细胞中短暂表达。VIP信号肽拮抗剂（VIPhyb）在体外增加T细胞增殖，并降低供体T细胞中白细胞介素10（IL10）的表达。在多个allo - BMT模型中，用VIPhyb治疗allo - BMT受体，或移植缺乏VIP的供体移植物（VIP - KO），可激活淋巴器官中的供体T细胞，减少T细胞向GvHD靶器官的归巢，并增强GvL而不增加GvHD。从移植物中对供体NK细胞或CD8 T细胞进行基因或体外清除可消除VIPhyb增强的GvL活性。VIPhyb治疗导致供体免疫细胞上程序性死亡受体1（PD - 1）和程序性死亡配体1（PD - L1）表达下调，效应分子表达增加，并扩增寡克隆CD8 T细胞，从而保护二次allo移植受体免受白血病侵害。因此，阻断VIP信号代表了一种新的药理学方法，可在allo - BMT中将GvL与GvHD分离，并增强适应性T细胞对白血病相关抗原的反应。《癌症研究》；76(23)；6802 - 6815。©2016美国癌症研究协会。
