title: Genetic Regulation of Fate Decisions in Therapeutic T Cells to Enhance Tumor Protection and Memory Formation.
abstract: A key challenge in the field of T-cell immunotherapy for cancer is creating a suitable platform for promoting differentiation of effector cells while at the same time enabling self-renewal needed for long-term memory. Although transfer of less differentiated memory T cells increases efficacy through greater expansion and persistence in vivo, the capacity of such cells to sustain effector functions within immunosuppressive tumor microenvironments may still be limiting. We have therefore directly compared the impact of effector versus memory differentiation of therapeutic T cells in tumor-bearing mice by introducing molecular switches that regulate cell fate decisions via mTOR. Ectopic expression of RAS homolog enriched in brain (RHEB) increased mTORC1 signaling, promoted a switch to aerobic glycolysis, and increased expansion of effector T cells. By rapidly infiltrating tumors, RHEB-transduced T cells significantly reduced the emergence of immunoedited escape variants. In contrast, expression of proline-rich Akt substrate of 40 kDa (PRAS40) inhibited mTORC1, promoted quiescence, and blocked tumor infiltration. Fate mapping studies following transient expression of PRAS40 demonstrated that mTORC1(low) T cells made no contribution to initial tumor control but instead survived to become memory cells proficient in generating recall immunity. Our data support the design of translational strategies for generating heterogeneous T-cell immunity against cancer, with the appropriate balance between promoting effector differentiation and self-renewal. Unlike pharmacologic inhibitors, the genetic approach described here allows for upregulation as well as inhibition of the mTORC1 pathway and is highly selective for the therapeutic T cells without affecting systemic mTORC1 functions.
authors.affiliation: Department of Haematology, Cancer Institute, University College London, London, United Kingdom. Institute of Immunity and Transplantation, University College London, London, United Kingdom.
authors.forename: Pedro
authors.initials: P
authors.lastname: Veliça
authors.affiliation: Institute of Immunity and Transplantation, University College London, London, United Kingdom.
authors.forename: Mathias
authors.initials: M
authors.lastname: Zech
authors.affiliation: Division of Infection and Immunity, University College London, London, United Kingdom.
authors.forename: Sian
authors.initials: S
authors.lastname: Henson
authors.affiliation: Institute of Immunity and Transplantation, University College London, London, United Kingdom.
authors.forename: Angelika
authors.initials: A
authors.lastname: Holler
authors.affiliation: Department of Haematology, Cancer Institute, University College London, London, United Kingdom. Institute of Immunity and Transplantation, University College London, London, United Kingdom.
authors.forename: Teresa
authors.initials: T
authors.lastname: Manzo
authors.affiliation: Institute of Immunity and Transplantation, University College London, London, United Kingdom.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Pike
authors.affiliation: Department of Haematology, Cancer Institute, University College London, London, United Kingdom. Institute of Immunity and Transplantation, University College London, London, United Kingdom.
authors.forename: Pedro
authors.initials: P
authors.lastname: Santos E Sousa
authors.affiliation: Department of Haematology, Cancer Institute, University College London, London, United Kingdom. Institute of Immunity and Transplantation, University College London, London, United Kingdom.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Niels
authors.initials: N
authors.lastname: Heinz
authors.affiliation: Experimental Hematology, Hannover Medical School, Hannover, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schiedlmeier
authors.affiliation: Department of Haematology, Cancer Institute, University College London, London, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Pule
authors.affiliation: Institute of Immunity and Transplantation, University College London, London, United Kingdom.
authors.forename: Hans
authors.initials: H
authors.lastname: Stauss
authors.affiliation: Department of Haematology, Cancer Institute, University College London, London, United Kingdom. Institute of Immunity and Transplantation, University College London, London, United Kingdom. r.chakraverty@ucl.ac.uk.
authors.forename: Ronjon
authors.initials: R
authors.lastname: Chakraverty
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000502:physiology* / Q000637:transplantation; D045744:Cell Line, Tumor; D006801:Humans; D007156:Immunologic Memory / Q000235:genetics* / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000379:methods*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D020559:Monomeric GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D046912:Multiprotein Complexes / Q000276:immunology; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000517:prevention & control; D009479:Neuropeptides / Q000096:biosynthesis / Q000235:genetics; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics; D000076205:Ras Homolog Enriched in Brain Protein; D058570:TOR Serine-Threonine Kinases / Q000276:immunology; D014161:Transduction, Genetic
chemical_list: D046912:Multiprotein Complexes; D009479:Neuropeptides; D010750:Phosphoproteins; D000076205:Ras Homolog Enriched in Brain Protein; C490213:Rheb protein, mouse; C508191:proline-rich Akt substrate, 40 kDa protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins