TY - JOUR
T1 - Generation and characterization of HLA-A2 transgenic mice expressing the human TCR 1G4 specific for the HLA-A2 restricted NY-ESO-1 157-165 tumor-specific peptide
AU - Shenderov, Eugene
AU - Kandasamy, Matheswaran
AU - Gileadi, Uzi
AU - Chen, Jili
AU - Shepherd, Dawn
AU - Gibbs, James
AU - Prota, Gennaro
AU - Silk, Jonathan D.
AU - Yewdell, Jonathan W.
AU - Cerundolo, Vincenzo
N1 - Funding Information:
Funding ES was supported by the Rhodes Trust, Oxford, UK and the Division of Intramural Research, NIAID, Bethesda, Maryland, USA. VC and UG are supported by MRC and MK JDS and VC are supported by the CRUK. JB and JWY are supported by the Division of Intramural Research, NIAID, Bethesda, Maryland, USA.
Publisher Copyright:
© 2021 BMJ Publishing Group. All rights reserved.
PY - 2021/6/4
Y1 - 2021/6/4
N2 - Background NY-ESO-1 is a tumor-specific, highly immunogenic, human germ cell antigen of the MAGE-1 family that is a promising vaccine and cell therapy candidate in clinical trial development. The mouse genome does not encode an NY-ESO-1 homolog thereby not subjecting transgenic T-cells to thymic tolerance mechanisms that might impair in-vivo studies. We hypothesized that an NY-ESO-1 T cell receptor (TCR) transgenic mouse would provide the unique opportunity to study avidity of TCR response against NY-ESO-1 for tumor vaccine and cellular therapy development against this clinically relevant and physiological human antigen. Methods To study in vitro and in vivo the requirements for shaping an effective T cell response against the clinically relevant NY-ESO-1, we generated a C57BL/6 HLA-A∗0201 background TCR transgenic mouse encoding the 1G4 TCR specific for the human HLA-A2 restricted, NY-ESO-1 157-165 SLLMWITQC (9C), initially identified in an NY-ESO-1 positive melanoma patient. Results The HLA-A∗0201 restricted TCR was positively selected on both CD4 + and CD8 + cells. Mouse 1G4 T cells were not activated by endogenous autoimmune targets or a large library of non-cognate viral antigens. In contrast, their activation by HLA-A2 NY-ESO-1 157-165 complexes was evident by proliferation, CD69 upregulation, interferon-γproduction, and interleukin-2 production, and could be tuned using a twofold higher affinity altered peptide ligand, NY-ESO-1 157-165V. NY-ESO-1 157-165V recombinant vaccination of syngeneic mice adoptively transferred with m1G4 CD8 + T cells controlled tumor growth in vivo. 1G4 transgenic mice suppressed growth of syngeneic methylcholanthrene (MCA) induced HHD tumor cells expressing the full-length human NY-ESO-1 protein but not MCA HHD tumor cells lacking NY-ESO-1. Conclusions The 1G4 TCR mouse model for the physiological human TCR against the clinically relevant antigen, NY-ESO-1, is a valuable tool with the potential to accelerate clinical development of NY-ESO-1-targeted T-cell and vaccine therapies.
AB - Background NY-ESO-1 is a tumor-specific, highly immunogenic, human germ cell antigen of the MAGE-1 family that is a promising vaccine and cell therapy candidate in clinical trial development. The mouse genome does not encode an NY-ESO-1 homolog thereby not subjecting transgenic T-cells to thymic tolerance mechanisms that might impair in-vivo studies. We hypothesized that an NY-ESO-1 T cell receptor (TCR) transgenic mouse would provide the unique opportunity to study avidity of TCR response against NY-ESO-1 for tumor vaccine and cellular therapy development against this clinically relevant and physiological human antigen. Methods To study in vitro and in vivo the requirements for shaping an effective T cell response against the clinically relevant NY-ESO-1, we generated a C57BL/6 HLA-A∗0201 background TCR transgenic mouse encoding the 1G4 TCR specific for the human HLA-A2 restricted, NY-ESO-1 157-165 SLLMWITQC (9C), initially identified in an NY-ESO-1 positive melanoma patient. Results The HLA-A∗0201 restricted TCR was positively selected on both CD4 + and CD8 + cells. Mouse 1G4 T cells were not activated by endogenous autoimmune targets or a large library of non-cognate viral antigens. In contrast, their activation by HLA-A2 NY-ESO-1 157-165 complexes was evident by proliferation, CD69 upregulation, interferon-γproduction, and interleukin-2 production, and could be tuned using a twofold higher affinity altered peptide ligand, NY-ESO-1 157-165V. NY-ESO-1 157-165V recombinant vaccination of syngeneic mice adoptively transferred with m1G4 CD8 + T cells controlled tumor growth in vivo. 1G4 transgenic mice suppressed growth of syngeneic methylcholanthrene (MCA) induced HHD tumor cells expressing the full-length human NY-ESO-1 protein but not MCA HHD tumor cells lacking NY-ESO-1. Conclusions The 1G4 TCR mouse model for the physiological human TCR against the clinically relevant antigen, NY-ESO-1, is a valuable tool with the potential to accelerate clinical development of NY-ESO-1-targeted T-cell and vaccine therapies.
KW - CD8-Positive T-Lymphocytes
KW - adoptive
KW - cellular
KW - immunity
KW - immunotherapy
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U2 - 10.1136/jitc-2021-002544
DO - 10.1136/jitc-2021-002544
M3 - Article
C2 - 34088742
AN - SCOPUS:85107761431
SN - 2051-1426
VL - 9
JO - Journal for immunotherapy of cancer
JF - Journal for immunotherapy of cancer
IS - 6
M1 - e002544
ER -