TY - JOUR
T1 - Transnuclear TRP1-specific CD8 T cells with high or low affinity TCRs show equivalent antitumor activity
AU - Dougan, Stephanie K.
AU - Dougan, Michael
AU - Kim, Jun
AU - Turner, Jacob A.
AU - Ogata, Souichi
AU - Cho, Hyun Il
AU - Jaenisch, Rudolf
AU - Celis, Esteban
AU - Ploegh, Hidde L.
PY - 2013/8/1
Y1 - 2013/8/1
N2 - 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.
AB - 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.
KW - B16
KW - T cell receptor
KW - melanoma
KW - somatic cell nuclear transfer
KW - tyrosinase related protein 1
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UR - http://www.scopus.com/inward/citedby.url?scp=84888065568&partnerID=8YFLogxK
U2 - 10.1158/2326-6066.CIR-13-0047
DO - 10.1158/2326-6066.CIR-13-0047
M3 - Article
C2 - 24459675
AN - SCOPUS:84888065568
SN - 2326-6066
VL - 1
SP - 99
EP - 111
JO - Cancer Immunology Research
JF - Cancer Immunology Research
IS - 2
ER -