title: The stoichiometric production of IL-2 and IFN-γ mRNA defines memory T cells that can self-renew after adoptive transfer in humans.
abstract: Adoptive immunotherapy using ex vivo-expanded tumor-reactive lymphocytes can mediate durable cancer regression in selected melanoma patients. Analyses of these trials have associated the in vivo engraftment ability of the transferred cells with their antitumor efficacy. Thus, there is intensive clinical interest in the prospective isolation of tumor-specific T cells that can reliably persist after transfer. Animal studies have suggested that central memory CD8(+) T cells (T(CM)) have divergent capabilities including effector differentiation to target antigen and stem cell-like self-renewal that enable long-term survival after adoptive transfer. We sought to isolate human melanoma-specific T(CM) to define their in vivo fate and function after autologous therapeutic transfer to metastatic patients. To facilitate the high-throughput identification of these rare cells from patients, we report that T(CM) have a defined stoichiometric production of interleukin-2 (IL-2) and interferon-γ (IFN-γ) mRNA after antigen stimulation. Melanoma-specific T cells screened for high relative IL-2 production had a T(CM) phenotype and superior in vitro proliferative capacity compared to cells with low IL-2 production. To investigate in vivo effector function and self-renewal capability, we allowed melanoma-specific T(CM) to undergo in vitro expansion and differentiation into lytic effector clones and then adoptively transferred them back into their hosts. These clones targeted skin melanocytes in all five patients and persisted long term and reacquired parental T(CM) attributes in four patients after transfer. These findings demonstrate the favorable engraftment fitness for human T(CM)-derived clones, but further efforts to improve their antitumor efficacy are still necessary.
authors.affiliation: Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20817, USA.
authors.forename: Anran
authors.initials: A
authors.lastname: Wang
authors.forename: Smita
authors.initials: S
authors.lastname: Chandran
authors.forename: Syed A
authors.initials: SA
authors.lastname: Shah
authors.forename: Yu
authors.initials: Y
authors.lastname: Chiu
authors.forename: Biman C
authors.initials: BC
authors.lastname: Paria
authors.forename: Tamara
authors.initials: T
authors.lastname: Aghamolla
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Alvarez-Downing
authors.forename: Chyi-Chia Richard
authors.initials: CC
authors.lastname: Lee
authors.forename: Sanmeet
authors.initials: S
authors.lastname: Singh
authors.forename: Thomas
authors.initials: T
authors.lastname: Li
authors.forename: Mark E
authors.initials: ME
authors.lastname: Dudley
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: Udai S
authors.initials: US
authors.lastname: Kammula
mesh_terms: D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation*; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D002469:Cell Separation; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D003872:Dermatitis / Q000235:genetics / Q000276:immunology; D005260:Female; D020869:Gene Expression Profiling; D057166:High-Throughput Screening Assays; D006801:Humans; D007156:Immunologic Memory / Q000235:genetics*; D016219:Immunotherapy, Adoptive / Q000009:adverse effects; D007371:Interferon-gamma / Q000235:genetics* / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D008875:Middle Aged; D010641:Phenotype; D011446:Prospective Studies; D012333:RNA, Messenger / Q000096:biosynthesis*; D012878:Skin Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D013997:Time Factors
chemical_list: C508594:IL2 protein, human; D007376:Interleukin-2; D012333:RNA, Messenger; D007371:Interferon-gamma