Potent Activation of Human T Cells by mRNA Encoding Constitutively Active CD40

Noam Levin, Hadas Weinstein-Marom, Aviad Pato, Orit Itzhaki, Michal J. Besser, Galit Eisenberg, Tamar Peretz, Michal Lotem, Gideon Gross

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

New strategies for augmenting the actual performance of therapeutic T cells in vivo are needed for improving clinical outcome of adoptive cell therapy. Cumulative findings suggest that CD40 plays an intrinsic role in T cell costimulation. Recently, we demonstrated the ability of truncated, auto-oligomerizing CD40 derivatives to induce strong activation of APCs in a ligandindependent manner. We reasoned that constitutively active CD40 (caCD40) can similarly exert enhancing effects on human antitumor T cells. To test this assumption, we transfected human T cells with in vitro-transcribed caCD40 mRNA. In polyclonal T cells, caCD40 triggered IFN-g secretion and upregulated CD25 and 4-1BB. In antimelanoma tumor-infiltrating lymphocytes (TILs), caCD40 induced massive production of IFN-γ, exerting a pronounced synergistic effect when coexpressed with constitutively active TLR4 devoid of its extracellular ligand binding. In unselected "young" TILs, caCD40 reproducibly increased surface expression of CD25, OX40, 4-1BB, CD127, and CD28. Three days post-mRNA electroporation of CD8 TILs, caCD40 elevated IFN-g and TNF-a production and cytolytic activity in the presence of autologous but not HLA-I-mismatched melanoma. Enhanced killing of autologous melanoma by young TILs was observed 4 d posttransfection. These findings suggest that caCD40 can function as a potent T cell adjuvant and provide essential guidelines for similar manipulation of other key members of the TNFR family. The Journal of Immunology, 2018, 201: 2959-2968.

Original languageEnglish (US)
Pages (from-to)2959-2968
Number of pages10
JournalJournal of Immunology
Volume201
Issue number10
DOIs
StatePublished - Nov 15 2018

Fingerprint

Tumor-Infiltrating Lymphocytes
T-Lymphocytes
Messenger RNA
Melanoma
Aptitude
Electroporation
Cell- and Tissue-Based Therapy
Allergy and Immunology
Guidelines
Ligands

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Levin, N., Weinstein-Marom, H., Pato, A., Itzhaki, O., Besser, M. J., Eisenberg, G., ... Gross, G. (2018). Potent Activation of Human T Cells by mRNA Encoding Constitutively Active CD40. Journal of Immunology, 201(10), 2959-2968. https://doi.org/10.4049/jimmunol.1701725

Potent Activation of Human T Cells by mRNA Encoding Constitutively Active CD40. / Levin, Noam; Weinstein-Marom, Hadas; Pato, Aviad; Itzhaki, Orit; Besser, Michal J.; Eisenberg, Galit; Peretz, Tamar; Lotem, Michal; Gross, Gideon.

In: Journal of Immunology, Vol. 201, No. 10, 15.11.2018, p. 2959-2968.

Research output: Contribution to journalArticle

Levin, N, Weinstein-Marom, H, Pato, A, Itzhaki, O, Besser, MJ, Eisenberg, G, Peretz, T, Lotem, M & Gross, G 2018, 'Potent Activation of Human T Cells by mRNA Encoding Constitutively Active CD40', Journal of Immunology, vol. 201, no. 10, pp. 2959-2968. https://doi.org/10.4049/jimmunol.1701725
Levin N, Weinstein-Marom H, Pato A, Itzhaki O, Besser MJ, Eisenberg G et al. Potent Activation of Human T Cells by mRNA Encoding Constitutively Active CD40. Journal of Immunology. 2018 Nov 15;201(10):2959-2968. https://doi.org/10.4049/jimmunol.1701725
Levin, Noam ; Weinstein-Marom, Hadas ; Pato, Aviad ; Itzhaki, Orit ; Besser, Michal J. ; Eisenberg, Galit ; Peretz, Tamar ; Lotem, Michal ; Gross, Gideon. / Potent Activation of Human T Cells by mRNA Encoding Constitutively Active CD40. In: Journal of Immunology. 2018 ; Vol. 201, No. 10. pp. 2959-2968.
@article{cfeaf221caf541ba8b63faa5a5d49683,
title = "Potent Activation of Human T Cells by mRNA Encoding Constitutively Active CD40",
abstract = "New strategies for augmenting the actual performance of therapeutic T cells in vivo are needed for improving clinical outcome of adoptive cell therapy. Cumulative findings suggest that CD40 plays an intrinsic role in T cell costimulation. Recently, we demonstrated the ability of truncated, auto-oligomerizing CD40 derivatives to induce strong activation of APCs in a ligandindependent manner. We reasoned that constitutively active CD40 (caCD40) can similarly exert enhancing effects on human antitumor T cells. To test this assumption, we transfected human T cells with in vitro-transcribed caCD40 mRNA. In polyclonal T cells, caCD40 triggered IFN-g secretion and upregulated CD25 and 4-1BB. In antimelanoma tumor-infiltrating lymphocytes (TILs), caCD40 induced massive production of IFN-γ, exerting a pronounced synergistic effect when coexpressed with constitutively active TLR4 devoid of its extracellular ligand binding. In unselected {"}young{"} TILs, caCD40 reproducibly increased surface expression of CD25, OX40, 4-1BB, CD127, and CD28. Three days post-mRNA electroporation of CD8 TILs, caCD40 elevated IFN-g and TNF-a production and cytolytic activity in the presence of autologous but not HLA-I-mismatched melanoma. Enhanced killing of autologous melanoma by young TILs was observed 4 d posttransfection. These findings suggest that caCD40 can function as a potent T cell adjuvant and provide essential guidelines for similar manipulation of other key members of the TNFR family. The Journal of Immunology, 2018, 201: 2959-2968.",
author = "Noam Levin and Hadas Weinstein-Marom and Aviad Pato and Orit Itzhaki and Besser, {Michal J.} and Galit Eisenberg and Tamar Peretz and Michal Lotem and Gideon Gross",
year = "2018",
month = "11",
day = "15",
doi = "10.4049/jimmunol.1701725",
language = "English (US)",
volume = "201",
pages = "2959--2968",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "10",

}

TY - JOUR

T1 - Potent Activation of Human T Cells by mRNA Encoding Constitutively Active CD40

AU - Levin, Noam

AU - Weinstein-Marom, Hadas

AU - Pato, Aviad

AU - Itzhaki, Orit

AU - Besser, Michal J.

AU - Eisenberg, Galit

AU - Peretz, Tamar

AU - Lotem, Michal

AU - Gross, Gideon

PY - 2018/11/15

Y1 - 2018/11/15

N2 - New strategies for augmenting the actual performance of therapeutic T cells in vivo are needed for improving clinical outcome of adoptive cell therapy. Cumulative findings suggest that CD40 plays an intrinsic role in T cell costimulation. Recently, we demonstrated the ability of truncated, auto-oligomerizing CD40 derivatives to induce strong activation of APCs in a ligandindependent manner. We reasoned that constitutively active CD40 (caCD40) can similarly exert enhancing effects on human antitumor T cells. To test this assumption, we transfected human T cells with in vitro-transcribed caCD40 mRNA. In polyclonal T cells, caCD40 triggered IFN-g secretion and upregulated CD25 and 4-1BB. In antimelanoma tumor-infiltrating lymphocytes (TILs), caCD40 induced massive production of IFN-γ, exerting a pronounced synergistic effect when coexpressed with constitutively active TLR4 devoid of its extracellular ligand binding. In unselected "young" TILs, caCD40 reproducibly increased surface expression of CD25, OX40, 4-1BB, CD127, and CD28. Three days post-mRNA electroporation of CD8 TILs, caCD40 elevated IFN-g and TNF-a production and cytolytic activity in the presence of autologous but not HLA-I-mismatched melanoma. Enhanced killing of autologous melanoma by young TILs was observed 4 d posttransfection. These findings suggest that caCD40 can function as a potent T cell adjuvant and provide essential guidelines for similar manipulation of other key members of the TNFR family. The Journal of Immunology, 2018, 201: 2959-2968.

AB - New strategies for augmenting the actual performance of therapeutic T cells in vivo are needed for improving clinical outcome of adoptive cell therapy. Cumulative findings suggest that CD40 plays an intrinsic role in T cell costimulation. Recently, we demonstrated the ability of truncated, auto-oligomerizing CD40 derivatives to induce strong activation of APCs in a ligandindependent manner. We reasoned that constitutively active CD40 (caCD40) can similarly exert enhancing effects on human antitumor T cells. To test this assumption, we transfected human T cells with in vitro-transcribed caCD40 mRNA. In polyclonal T cells, caCD40 triggered IFN-g secretion and upregulated CD25 and 4-1BB. In antimelanoma tumor-infiltrating lymphocytes (TILs), caCD40 induced massive production of IFN-γ, exerting a pronounced synergistic effect when coexpressed with constitutively active TLR4 devoid of its extracellular ligand binding. In unselected "young" TILs, caCD40 reproducibly increased surface expression of CD25, OX40, 4-1BB, CD127, and CD28. Three days post-mRNA electroporation of CD8 TILs, caCD40 elevated IFN-g and TNF-a production and cytolytic activity in the presence of autologous but not HLA-I-mismatched melanoma. Enhanced killing of autologous melanoma by young TILs was observed 4 d posttransfection. These findings suggest that caCD40 can function as a potent T cell adjuvant and provide essential guidelines for similar manipulation of other key members of the TNFR family. The Journal of Immunology, 2018, 201: 2959-2968.

UR - http://www.scopus.com/inward/record.url?scp=85056252352&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85056252352&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.1701725

DO - 10.4049/jimmunol.1701725

M3 - Article

C2 - 30305327

AN - SCOPUS:85056252352

VL - 201

SP - 2959

EP - 2968

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 10

ER -