title: The advantages of PD1 activating chimeric receptor (PD1-ACR) engineered lymphocytes for PDL1(+) cancer therapy.
abstract: Tumors exploit immunoregulatory checkpoints to attenuate T cell responses as a means of circumventing immunologic rejection. By activating the inhibitory costimulatory pathway of Programmed Death 1 (PD1)/PDL1 which provides tumor cells an escape mechanism from immune surveillance, Programmed Death Ligand1 (PDL1)(+) tumors hamper activated tumor-specific T cell functions and render them functionally exhausted. To overcome the inhibitory costimulatory effects of PDL1 on the adoptively transferred T cells, we sought to convert PD1 to a T cell costimulatory receptor by exchanging its transmembrane and cytoplasmic tail with CD28 and 4-1BB signaling domains (PD1-CD28-4-1BB, PD1-ACR), anticipating the genetically modified effector T lymphocytes expressing PD1-ACR would exhibit enhanced functional attributes. And the results showed that PD1-ACR expressed T cells retained the ability to bind PDL1, resulting in T cell activation as evidenced by the elevated activity of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), the augmentation of cytokine secretion and the increased proliferative capacity. Moreover, when systemically administered in the mouse model of glioblastoma metastases, PD1-ACR T cells localized at the area of U87 invasive tumor, which results in suppressed tumor growth and enhanced survival of mice with established U87 glioblastoma. Together, these data demonstrated that PD1-ACR has a high potential to serve as a novel strategy to overcome PDL1 mediated immunosuppression of T cells for cancer therapy.
authors.affiliation: Stem Cell Engineering Research Center, School of Medicine, Anhui University of Science & Technology Huainan 232001, China ; State Key Laboratory of Virology/Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University Wuhan 430071, PR China.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Tang
authors.affiliation: Department of Galactophore, Huai'an Maternity and Child Healthcare Hospital Affiliated to Yangzhou University Medical Academy Huaian 223002, China.
authors.forename: Qingguo
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Medical Genetics, Tongji Medical College, Huazhong University of Science and Technology Wuhan 430074, China.
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Clinical Laboratory, The Affiliated Huai'an Hospital of Xuzhou Medical College Huai'an 223002, China.
authors.forename: Donghui
authors.initials: D
authors.lastname: Zheng
authors.affiliation: Stem Cell Engineering Research Center, School of Medicine, Anhui University of Science & Technology Huainan 232001, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Dai
authors.affiliation: Stem Cell Engineering Research Center, School of Medicine, Anhui University of Science & Technology Huainan 232001, China.
authors.forename: Wenxuan
authors.initials: W
authors.lastname: Ni
authors.affiliation: Stem Cell Engineering Research Center, School of Medicine, Anhui University of Science & Technology Huainan 232001, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Wei
authors.affiliation: Clinical Laboratory, The Affiliated Huai'an Hospital of Xuzhou Medical College Huai'an 223002, China.
authors.forename: Yubao
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Clinical Laboratory, The Affiliated Huai'an Hospital of Xuzhou Medical College Huai'an 223002, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Virology/Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University Wuhan 430071, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Hou
authors.affiliation: Stem Cell Engineering Research Center, School of Medicine, Anhui University of Science & Technology Huainan 232001, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Britton Chance Center for Biomedical Photonics at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics & Molecular Imaging Key Laboratory, Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology Wuhan 430074, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Feng
authors.affiliation: Clinical Laboratory, The Affiliated Huai'an Hospital of Xuzhou Medical College Huai'an 223002, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Liang
keywords: Programmed Death Ligand 1; activating chimeric receptor; cytotoxicity; phosphoinositide 3-kinase