title: Akt inhibition enhances expansion of potent tumor-specific lymphocytes with memory cell characteristics.
abstract: Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) results in complete regression of advanced cancer in some patients, but the efficacy of this potentially curative therapy may be limited by poor persistence of TIL after adoptive transfer. Pharmacologic inhibition of the serine/threonine kinase Akt has recently been shown to promote immunologic memory in virus-specific murine models, but whether this approach enhances features of memory (e.g., long-term persistence) in TIL that are characteristically exhausted and senescent is not established. Here, we show that pharmacologic inhibition of Akt enables expansion of TIL with the transcriptional, metabolic, and functional properties characteristic of memory T cells. Consequently, Akt inhibition results in enhanced persistence of TIL after adoptive transfer into an immunodeficient animal model and augments antitumor immunity of CD8 T cells in a mouse model of cell-based immunotherapy. Pharmacologic inhibition of Akt represents a novel immunometabolomic approach to enhance the persistence of antitumor T cells and improve the efficacy of cell-based immunotherapy for metastatic cancer.
authors.affiliation: National Cancer Institute (NCI), NIH, Bethesda, Maryland. Department of Surgery, University of California Los Angeles, Los Angeles, California. Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom. joe.crompton@nih.gov sukumarm2@mail.nih.gov restifo@nih.gov.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Crompton
authors.affiliation: National Cancer Institute (NCI), NIH, Bethesda, Maryland. joe.crompton@nih.gov sukumarm2@mail.nih.gov restifo@nih.gov.
authors.forename: Madhusudhanan
authors.initials: M
authors.lastname: Sukumar
authors.affiliation: National Cancer Institute (NCI), NIH, Bethesda, Maryland.
authors.forename: Rahul
authors.initials: R
authors.lastname: Roychoudhuri
authors.affiliation: National Cancer Institute (NCI), NIH, Bethesda, Maryland. Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Clever
authors.affiliation: National Cancer Institute (NCI), NIH, Bethesda, Maryland.
authors.forename: Alena
authors.initials: A
authors.lastname: Gros
authors.affiliation: National Cancer Institute (NCI), NIH, Bethesda, Maryland.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Eil
authors.affiliation: National Cancer Institute (NCI), NIH, Bethesda, Maryland.
authors.forename: Eric
authors.initials: E
authors.lastname: Tran
authors.affiliation: National Cancer Institute (NCI), NIH, Bethesda, Maryland.
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Hanada
authors.affiliation: National Cancer Institute (NCI), NIH, Bethesda, Maryland.
authors.forename: Zhiya
authors.initials: Z
authors.lastname: Yu
authors.affiliation: National Cancer Institute (NCI), NIH, Bethesda, Maryland.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Palmer
authors.affiliation: National Cancer Institute (NCI), NIH, Bethesda, Maryland.
authors.forename: Sid P
authors.initials: SP
authors.lastname: Kerkar
authors.affiliation: Metabolon Incorporated, Durham, North Carolina.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Michalek
authors.affiliation: National Cancer Institute (NCI), NIH, Bethesda, Maryland.
authors.forename: Trevor
authors.initials: T
authors.lastname: Upham
authors.affiliation: National Cancer Institute (NCI), NIH, Bethesda, Maryland.
authors.forename: Anthony
authors.initials: A
authors.lastname: Leonardi
authors.affiliation: National Cancer Institute (NCI), NIH, Bethesda, Maryland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Acquavella
authors.affiliation: Sidra Medical and Research Centre, Doha, Qatar.
authors.forename: Ena
authors.initials: E
authors.lastname: Wang
authors.affiliation: Sidra Medical and Research Centre, Doha, Qatar.
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Marincola
authors.affiliation: National Cancer Institute (NCI), NIH, Bethesda, Maryland.
authors.forename: Luca
authors.initials: L
authors.lastname: Gattinoni
authors.affiliation: National Cancer Institute (NCI), NIH, Bethesda, Maryland.
authors.forename: Pawel
authors.initials: P
authors.lastname: Muranski
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, Jupiter, Florida.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Sundrud
authors.affiliation: National Cancer Institute (NCI), NIH, Bethesda, Maryland. Clinical Investigator Development Program, NCI, NIH, Bethesda, Maryland.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Klebanoff
authors.affiliation: National Cancer Institute (NCI), NIH, Bethesda, Maryland.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.affiliation: Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom.
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Fearon
authors.affiliation: National Cancer Institute (NCI), NIH, Bethesda, Maryland.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
mesh_terms: D000818:Animals; D006801:Humans; D007156:Immunologic Memory; D016219:Immunotherapy, Adoptive / Q000379:methods*; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000276:immunology; D011897:Random Allocation; D014407:Tumor Cells, Cultured
chemical_list: D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt