Transnuclear TRP1-specific CD8 T cells with high or low affinity TCRs show equivalent antitumor activity.
We have generated, via somatic cell nuclear transfer, two independent lines of transnuclear (TN) mice, using as nuclear donors CD8 T cells, sorted by tetramer staining, that recognize the endogenous melanoma antigen TRP1. These two lines of nominally identical specificity differ greatly in their affinity for antigen (TRP1(high) or TRP1(low)) as inferred from tetramer dissociation and peptide responsiveness. Ex vivo-activated CD8 T cells from either TRP1(high) or TRP1(low) mice show cytolytic activity in 3D tissue culture and in vivo, and slow the progression of subcutaneous B16 melanoma. Although naïve TRP1(low) CD8 T cells do not affect tumor growth, upon activation these cells function indistinguishably from TRP1(high) cells in vivo, limiting tumor cell growth and increasing mouse survival. The anti-tumor effect of both TRP1(high) and TRP1(low) CD8 T cells is enhanced in RAG-deficient hosts. However, tumor outgrowth eventually occurs, likely due to T cell exhaustion. The TRP1 TN mice are an excellent model for examining the functional attributes of T cells conferred by TCR affinity, and they may serve as a platform for screening immunomodulatory cancer therapies.
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142.
Stephanie K
SK
Dougan
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142 ; Department of Medicine, Massachusetts General Hospital, Boston, MA.
Michael
M
Dougan
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142 ; Massachusetts Institute of Technology, Cambridge, MA.
Jun
J
Kim
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142 ; University of Cincinnati, 2600 Clifton Ave, Cincinnati, OH 45221.
Jacob A
JA
Turner
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142 ; Janssen Research and Development, division of Janssen Pharmaceutica NV, Turnhoutseweg 30, Beerse B2340, Belgium.
Souichi
S
Ogata
Dept. of Immunology, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL 33612.
Hyun-Il
HI
Cho
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142.
Rudolf
R
Jaenisch
Dept. of Immunology, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL 33612.
Esteban
E
Celis
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142.
Hidde L
HL
Ploegh
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002467:Cell Nucleus / Q000276:immunology; D005260:Female; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D014357:Trypsin / Q000276:immunology*
D011948:Receptors, Antigen, T-Cell; D014357:Trypsin
B16; T cell receptor; melanoma; somatic cell nuclear transfer; tyrosinase related protein 1