title: Adoptively transferred effector cells derived from naive rather than central memory CD8+ T cells mediate superior antitumor immunity.
abstract: Effector cells derived from central memory CD8(+) T cells were reported to engraft and survive better than those derived from effector memory populations, suggesting that they are superior for use in adoptive immunotherapy studies. However, previous studies did not evaluate the relative efficacy of effector cells derived from naïve T cells. We sought to investigate the efficacy of tumor-specific effector cells derived from naïve or central memory T-cell subsets using transgenic or retrovirally transduced T cells engineered to express a tumor-specific T-cell receptor. We found that naïve, rather than central memory T cells, gave rise to an effector population that mediated superior antitumor immunity upon adoptive transfer. Effector cells developed from naïve T cells lost the expression of CD62L more rapidly than those derived from central memory T cells, but did not acquire the expression of KLRG-1, a marker for terminal differentiation and replicative senescence. Consistent with this KLRG-1(-) phenotype, naïve-derived cells were capable of a greater proliferative burst and had enhanced cytokine production after adoptive transfer. These results indicate that insertion of genes that confer antitumor specificity into naïve rather than central memory CD8(+) T cells may allow superior efficacy upon adoptive transfer.
authors.affiliation: National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Christian S
authors.initials: CS
authors.lastname: Hinrichs
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Borman
authors.forename: Lydie
authors.initials: L
authors.lastname: Cassard
authors.forename: Luca
authors.initials: L
authors.lastname: Gattinoni
authors.forename: Rosanne
authors.initials: R
authors.lastname: Spolski
authors.forename: Zhiya
authors.initials: Z
authors.lastname: Yu
authors.forename: Luis
authors.initials: L
authors.lastname: Sanchez-Perez
authors.forename: Pawel
authors.initials: P
authors.lastname: Muranski
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Kern
authors.forename: Carol
authors.initials: C
authors.lastname: Logun
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Palmer
authors.forename: Yun
authors.initials: Y
authors.lastname: Ji
authors.forename: Robert N
authors.initials: RN
authors.lastname: Reger
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Leonard
authors.forename: Robert L
authors.initials: RL
authors.lastname: Danner
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D030801:Animals, Genetically Modified; D001324:Autoantigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D016130:Immunophenotyping; D016219:Immunotherapy, Adoptive / Q000379:methods*; D009369:Neoplasms / Q000276:immunology*; D009374:Neoplasms, Experimental / Q000276:immunology; D011323:Primates / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D015996:Survival Rate
chemical_list: D001324:Autoantigens; D011948:Receptors, Antigen, T-Cell