title: Delineation of antigen-specific and antigen-nonspecific CD8(+) memory T-cell responses after cytokine-based cancer immunotherapy.
abstract: Memory T cells exhibit tremendous antigen specificity within the immune system and accumulate with age. Our studies reveal an antigen-independent expansion of memory, but not naive, CD8(+) T cells after several immunotherapeutic regimens for cancer resulting in a distinctive phenotype. Signaling through T-cell receptors (TCRs) or CD3 in both mouse and human memory CD8(+) T cells markedly up-regulated programmed death-1 (PD-1) and CD25 (IL-2 receptor α chain), and led to antigen-specific tumor cell killing. In contrast, exposure to cytokine alone in vitro or with immunotherapy in vivo did not up-regulate these markers but resulted in expanded memory CD8(+) T cells expressing NKG2D, granzyme B, and possessing broadly lytic capabilities. Blockade of NKG2D in mice also resulted in significantly diminished antitumor effects after immunotherapy. Treatment of TCR-transgenic mice bearing nonantigen expressing tumors with immunotherapy still resulted in significant antitumor effects. Human melanoma tissue biopsies obtained from patients after topically applied immunodulatory treatment resulted in increased numbers of these CD8(+) CD25(-) cells within the tumor site. These findings demonstrate that memory CD8(+) T cells can express differential phenotypes indicative of adaptive or innate effectors based on the nature of the stimuli in a process conserved across species.
authors.affiliation: Department of Dermatology, University of California, Davis, Sacramento, CA 95817, USA.
authors.forename: Julia K
authors.initials: JK
authors.lastname: Tietze
authors.forename: Danice E C
authors.initials: DE
authors.lastname: Wilkins
authors.forename: Gail D
authors.initials: GD
authors.lastname: Sckisel
authors.forename: Myriam N
authors.initials: MN
authors.lastname: Bouchlaka
authors.forename: Kory L
authors.initials: KL
authors.lastname: Alderson
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Weiss
authors.forename: Erik
authors.initials: E
authors.lastname: Ames
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Bruhn
authors.forename: Noah
authors.initials: N
authors.lastname: Craft
authors.forename: Robert H
authors.initials: RH
authors.lastname: Wiltrout
authors.forename: Dan L
authors.initials: DL
authors.lastname: Longo
authors.forename: Lewis L
authors.initials: LL
authors.lastname: Lanier
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: Doug
authors.initials: D
authors.lastname: Redelman
authors.forename: William J
authors.initials: WJ
authors.lastname: Murphy
mesh_terms: D000818:Animals; D016827:CD8 Antigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000627:therapeutic use*; D004311:Double-Blind Method; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D010919:Placebos; D016032:Randomized Controlled Trials as Topic; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology* / Q000502:physiology; D013997:Time Factors
chemical_list: D016827:CD8 Antigens; D016207:Cytokines; D010919:Placebos