c-MPL provides tumor-targeted T-cell receptor-transgenic T cells with costimulation and cytokine signals.

Détails

Document(s) secondaire(s)
Télécharger: Nishimura et al-Blood-2018.pdf (2028.67 [Ko])
Etat: Public
Version: de l'auteur⸱e
Licence: Non spécifiée
ID Serval
serval:BIB_8E24CEF6F494
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
c-MPL provides tumor-targeted T-cell receptor-transgenic T cells with costimulation and cytokine signals.
Périodique
Blood
Auteur⸱e⸱s
Nishimura C.D., Brenner D.A., Mukherjee M., Hirsch R.A., Ott L., Wu M.F., Liu H., Dakhova O., Orange J.S., Brenner M.K., Lin C.Y., Arber C.
ISSN
1528-0020 (Electronic)
ISSN-L
0006-4971
Statut éditorial
Publié
Date de publication
21/12/2017
Peer-reviewed
Oui
Volume
130
Numéro
25
Pages
2739-2749
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
Adoptively transferred T-cell receptor (TCR)-engineered T cells depend on host-derived costimulation and cytokine signals for their full and sustained activation. However, in patients with cancer, both signals are frequently impaired. Hence, we developed a novel strategy that combines both essential signals in 1 transgene by expressing the nonlymphoid hematopoietic growth factor receptor c-MPL (myeloproliferative leukemia), the receptor for thrombopoietin (TPO), in T cells. c-MPL signaling activates pathways shared with conventional costimulatory and cytokine receptor signaling. Thus, we hypothesized that host-derived TPO, present in the tumor microenvironment, or pharmacological c-MPL agonists approved by the US Food and Drug Administration could deliver both signals to c-MPL-engineered TCR-transgenic T cells. We found that c-MPL <sup>+</sup> polyclonal T cells expand and proliferate in response to TPO, and persist longer after adoptive transfer in immunodeficient human TPO-transgenic mice. In TCR-transgenic T cells, c-MPL activation enhances antitumor function, T-cell expansion, and cytokine production and preserves a central memory phenotype. c-MPL signaling also enables sequential tumor cell killing, enhances the formation of effective immune synapses, and improves antileukemic activity in vivo in a leukemia xenograft model. We identify the type 1 interferon pathway as a molecular mechanism by which c-MPL mediates immune stimulation in T cells. In conclusion, we present a novel immunotherapeutic strategy using c-MPL-enhanced transgenic T cells responding to either endogenously produced TPO (a microenvironment factor in hematologic malignancies) or c-MPL-targeted pharmacological agents.
Mots-clé
Animals, Cell Proliferation/drug effects, Cytokines/metabolism, Heterografts, Humans, Immunotherapy, Adoptive/methods, Interferon Type I/metabolism, Mice, Receptors, Thrombopoietin/agonists, Receptors, Thrombopoietin/metabolism, Receptors, Thrombopoietin/physiology, Signal Transduction/drug effects
Pubmed
Web of science
Création de la notice
01/11/2019 9:50
Dernière modification de la notice
02/11/2019 6:26
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