title: Human effector T cells derived from central memory cells rather than CD8(+)T cells modified by tumor-specific TCR gene transfer possess superior traits for adoptive immunotherapy.
abstract: Adoptive cell therapy provides an attractive treatment of cancer, and our expanding capacity to target tumor antigens is driven by genetically engineered human T lymphocytes that express genes encoding tumor-specific T cell receptors (TCRs). The intrinsic properties of cultured T cells used for therapy were reported to have tremendous influences on their persistence and antitumor efficacy in vivo. In this study, we isolated CD8(+) central memory T cells from peripheral blood lymphocytes of healthy donors, and then transferred with the gene encoding TCR specific for tumor antigen using recombinant adenovirus vector Ad5F35-TRAV-TRBV. We found effector T cells derived from central memory T cells improved cell viability, maintained certain level of CD62L expression, and reacquired the CD62L(+)CD44(high) phenotype of central memory T cells after effector T cells differentiation. We then compared the antitumor reactivity of central memory T cells and CD8(+)T cells after TCR gene transferred. The results indicated that tumor-specific TCR gene being transferred to central memory T cells effectively increased the specific killing of antigen positive tumor cells and the expression of cytolytic granule protein. Furthermore, TCR gene transferred central memory T cells were more effective than TCR gene transferred CD8(+)T cells in CTL activity and effector cytokine secretion. These results implicated that isolating central memory T cells rather than CD8(+)T cells for insertion of gene encoding tumor-specific TCR may provide a superior tumor-reactive T cell population for adoptive transfer.
authors.affiliation: School of Life Science and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China; Southern Medical University, Guangzhou, China; Institute of Bio-Pharmaceutical, Guangdong Pharmaceutical University, Guangzhou, China; Guangdong Provincial Key Laboratory of Biotechnology Candidate Drug Research, Guangzhou, China.
authors.forename: Fenglin
authors.initials: F
authors.lastname: Wu
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Zhang
authors.forename: Hongwei
authors.initials: H
authors.lastname: Shao
authors.forename: Huaben
authors.initials: H
authors.lastname: Bo
authors.forename: Han
authors.initials: H
authors.lastname: Shen
authors.forename: Jiandong
authors.initials: J
authors.lastname: Li
authors.forename: Yichen
authors.initials: Y
authors.lastname: Liu
authors.forename: Teng
authors.initials: T
authors.lastname: Wang
authors.forename: Wenli
authors.initials: W
authors.lastname: Ma
authors.forename: Shulin
authors.initials: S
authors.lastname: Huang
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000951:Antigens, Neoplasm / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007156:Immunologic Memory; D016219:Immunotherapy, Adoptive; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000628:therapy; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D000951:Antigens, Neoplasm; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell
keywords: AFP; CAR; CD8(+)T cell; CTL; Calcein-AM; IFN-γ; IL-2; Immunotherapy; LNs; T cell receptor; T(CM); T(EM); TCR; TE; TIL; TM; TN; Transfer; alpha-fetoprotein; calcein–acetoxymethyl ester; central memory T cell; coxsackie/adenovirus receptors; cytotoxic lymphocytes; effector T cell; effector memory T cell; interferon-gamma; interlukin-2; lymph nodes; mAb; memory T cell; monoclonal antibody; naïve T cell; tumor-infiltrating lymphocyte