TY - JOUR
T1 - T-cell receptor affinity and avidity defines antitumor response and autoimmunity in T-cell immunotherapy
AU - Zhong, Shi
AU - Malecek, Karolina
AU - Johnson, Laura A.
AU - Yu, Zhiya
AU - De Miera, Eleazar Vega Saenz
AU - Darvishian, Farbod
AU - McGary, Katelyn
AU - Huang, Kevin
AU - Boyer, Josh
AU - Corse, Emily
AU - Shao, Yongzhao
AU - Rosenberg, Steven A.
AU - Restifo, Nicholas P.
AU - Osman, Iman
AU - Krogsgaard, Michelle
PY - 2013/4/23
Y1 - 2013/4/23
N2 - T cells expressing antigen-specific T-cell receptors (TCRs) can mediate effective tumor regression, but they often also are accompanied by autoimmune responses. To determine the TCR affinity threshold defining the optimal balance between effective antitumor activity and autoimmunity in vivo, we used a unique self-antigen system comprising seven human melanoma gp100(209-217)-specific TCRs spanning physiological affinities (1-100 μM). We found that in vitro and in vivo T-cell responses are determined by TCR affinity, except in one case that was compensated by substantial CD8 involvement. Strikingly, we found that T-cell antitumor activity and autoimmunity are closely coupled but plateau at a defined TCR affinity of 10 μM, likely due to diminished contribution of TCR affinity to avidity above the threshold. Together, these results suggest that a relatively low-affinity threshold is necessary for the immune system to avoid self-damage, given the close relationship between antitumor activity and autoimmunity. The low threshold, in turn, indicates that adoptive T-cell therapy treatment strategies using in vitro-gen-erated high-affinity TCRs do not necessarily improve efficacy.
AB - T cells expressing antigen-specific T-cell receptors (TCRs) can mediate effective tumor regression, but they often also are accompanied by autoimmune responses. To determine the TCR affinity threshold defining the optimal balance between effective antitumor activity and autoimmunity in vivo, we used a unique self-antigen system comprising seven human melanoma gp100(209-217)-specific TCRs spanning physiological affinities (1-100 μM). We found that in vitro and in vivo T-cell responses are determined by TCR affinity, except in one case that was compensated by substantial CD8 involvement. Strikingly, we found that T-cell antitumor activity and autoimmunity are closely coupled but plateau at a defined TCR affinity of 10 μM, likely due to diminished contribution of TCR affinity to avidity above the threshold. Together, these results suggest that a relatively low-affinity threshold is necessary for the immune system to avoid self-damage, given the close relationship between antitumor activity and autoimmunity. The low threshold, in turn, indicates that adoptive T-cell therapy treatment strategies using in vitro-gen-erated high-affinity TCRs do not necessarily improve efficacy.
KW - Adoptive cell transfer
KW - Kinetic threshold
KW - Ocular autoimmunity
KW - Tumor immunity
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U2 - 10.1073/pnas.1221609110
DO - 10.1073/pnas.1221609110
M3 - Article
C2 - 23576742
AN - SCOPUS:84876859096
SN - 0027-8424
VL - 110
SP - 6973
EP - 6978
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 17
ER -