title: Memory T cell-driven differentiation of naive cells impairs adoptive immunotherapy.
abstract: Adoptive cell transfer (ACT) of purified naive, stem cell memory, and central memory T cell subsets results in superior persistence and antitumor immunity compared with ACT of populations containing more-differentiated effector memory and effector T cells. Despite a clear advantage of the less-differentiated populations, the majority of ACT trials utilize unfractionated T cell subsets. Here, we have challenged the notion that the mere presence of less-differentiated T cells in starting populations used to generate therapeutic T cells is sufficient to convey their desirable attributes. Using both mouse and human cells, we identified a T cell-T cell interaction whereby antigen-experienced subsets directly promote the phenotypic, functional, and metabolic differentiation of naive T cells. This process led to the loss of less-differentiated T cell subsets and resulted in impaired cellular persistence and tumor regression in mouse models following ACT. The T memory-induced conversion of naive T cells was mediated by a nonapoptotic Fas signal, resulting in Akt-driven cellular differentiation. Thus, induction of Fas signaling enhanced T cell differentiation and impaired antitumor immunity, while Fas signaling blockade preserved the antitumor efficacy of naive cells within mixed populations. These findings reveal that T cell subsets can synchronize their differentiation state in a process similar to quorum sensing in unicellular organisms and suggest that disruption of this quorum-like behavior among T cells has potential to enhance T cell-based immunotherapies.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Klebanoff
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Scott
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Leonardi
authors.forename: Tori N
authors.initials: TN
authors.lastname: Yamamoto
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Cruz
authors.forename: Claudia
authors.initials: C
authors.lastname: Ouyang
authors.forename: Madhu
authors.initials: M
authors.lastname: Ramaswamy
authors.forename: Rahul
authors.initials: R
authors.lastname: Roychoudhuri
authors.forename: Yun
authors.initials: Y
authors.lastname: Ji
authors.forename: Robert L
authors.initials: RL
authors.lastname: Eil
authors.forename: Madhusudhanan
authors.initials: M
authors.lastname: Sukumar
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Crompton
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Palmer
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Borman
authors.forename: David
authors.initials: D
authors.lastname: Clever
authors.forename: Stacy K
authors.initials: SK
authors.lastname: Thomas
authors.forename: Shashankkumar
authors.initials: S
authors.lastname: Patel
authors.forename: Zhiya
authors.initials: Z
authors.lastname: Yu
authors.forename: Pawel
authors.initials: P
authors.lastname: Muranski
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.forename: Ena
authors.initials: E
authors.lastname: Wang
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Marincola
authors.forename: Alena
authors.initials: A
authors.lastname: Gros
authors.forename: Luca
authors.initials: L
authors.lastname: Gattinoni
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: Richard M
authors.initials: RM
authors.lastname: Siegel
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D053222:Fas Ligand Protein / Q000502:physiology; D005260:Female; D007156:Immunologic Memory; D016219:Immunotherapy, Adoptive; D008546:Melanoma, Experimental / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D019014:fas Receptor / Q000502:physiology
chemical_list: D053222:Fas Ligand Protein; C491899:Fas protein, mouse; D019014:fas Receptor; D051057:Proto-Oncogene Proteins c-akt