A coreceptor-independent transgenic human TCR mediates anti-tumor and anti-self immunity in mice.
Recent advancements in T cell immunotherapy suggest that T cells engineered with high-affinity TCR can offer better tumor regression. However, whether a high-affinity TCR alone is sufficient to control tumor growth, or the T cell subset bearing the TCR is also important remains unclear. Using the human tyrosinase epitope-reactive, CD8-independent, high-affinity TCR isolated from MHC class I-restricted CD4(+) T cells obtained from tumor-infiltrating lymphocytes (TIL) of a metastatic melanoma patient, we developed a novel TCR transgenic mouse with a C57BL/6 background. This HLA-A2-restricted TCR was positively selected on both CD4(+) and CD8(+) single-positive cells. However, when the TCR transgenic mouse was developed with a HLA-A2 background, the transgenic TCR was primarily expressed by CD3(+)CD4(-)CD8(-) double-negative T cells. TIL 1383I TCR transgenic CD4(+), CD8(+), and CD4(-)CD8(-) T cells were functional and retained the ability to control tumor growth without the need for vaccination or cytokine support in vivo. Furthermore, the HLA-A2(+)/human tyrosinase TCR double-transgenic mice developed spontaneous hair depigmentation and had visual defects that progressed with age. Our data show that the expression of the high-affinity TIL 1383I TCR alone in CD3(+) T cells is sufficient to control the growth of murine and human melanoma, and the presence or absence of CD4 and CD8 coreceptors had little effect on its functional capacity.
Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA. mehrotr@musc.edu
Shikhar
S
Mehrotra
Amir A
AA
Al-Khami
Jared
J
Klarquist
Shahid
S
Husain
Osama
O
Naga
Jonathan M
JM
Eby
Anuradha K
AK
Murali
Gretchen E
GE
Lyons
Mingli
M
Li
Natali D
ND
Spivey
Håkan
H
Norell
Telma
T
Martins da Palma
Georgiana
G
Onicescu
C Marcela
CM
Diaz-Montero
Elizabeth
E
Garrett-Mayer
David J
DJ
Cole
I Caroline
IC
Le Poole
Michael I
MI
Nishimura
D000818:Animals; D015551:Autoimmunity; D017252:CD3 Complex / Q000276:immunology; D005434:Flow Cytometry; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008545:Melanoma / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology*
D017252:CD3 Complex; D015789:HLA-A2 Antigen; D011948:Receptors, Antigen, T-Cell