title: Implication of combined PD-L1/PD-1 blockade with cytokine-induced killer cells as a synergistic immunotherapy for gastrointestinal cancer.
abstract: Cytokine-induced killer (CIK) cells represent a realistic approach in cancer immunotherapy with confirmed survival benefits in the context of metastatic solid tumors. However, therapeutic effects are limited to a fraction of patients. In this study, immune-resistance elements and ideal combination therapies were explored. Initially, phenotypic analysis was performed to document CD3, CD56, NKG2D, DNAM-1, PD-L1, PD-1, CTLA-4, TIM-3, 2B4, and LAG-3 on CIK cells. Upon engagement of CIK cells with the tumor cells, expression of PD-1 on CIK cells and PD-L1 on both cells were up-regulated. Over-expression of PD-L1 levels on tumor cells via lentiviral transduction inhibited tumoricidal activity of CIK cells, and neutralizing of PD-L1/PD-1 signaling axis could enhance their tumor-killing effect. Conversely, blockade of NKG2D, a major activating receptor of CIK cells, largely caused dysfunction of CIK cells. Functional study showed an increase of NKG2D levels along with PD-L1/PD-1 blockade in the presence of other immune effector molecule secretion. Additionally, combined therapy of CIK infusion and PD-L1/PD-1 blockade caused a delay of in vivo tumor growth and exhibited a survival advantage over untreated mice. These results provide a preclinical proof-of-concept for simultaneous PD-L1/PD-1 pathways blockade along with CIK infusion as a novel immunotherapy for unresectable cancers.
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Congqi
authors.initials: C
authors.lastname: Dai
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Fengjuan
authors.initials: F
authors.lastname: Lin
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Ruixuan
authors.initials: R
authors.lastname: Geng
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Ge
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Tang
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Jinjia
authors.initials: J
authors.lastname: Chang
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Xinyang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.|Department of Oncology, Tongji University Tianyou Hospital, Shanghai, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors* / Q000235:genetics; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000628:therapy*; D045325:HCT116 Cells; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D008819:Mice, Nude; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000037:antagonists & inhibitors / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; D016207:Cytokines; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D034741:RNA, Small Interfering
keywords: CIK; NKG2D; PD-L1/PD-1; gastrointestinal tumor; immunotherapy