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T cell receptor affinity and avidity defines antitumor response and autoimmunity in T cell immunotherapy
© Krogsgaard et al; licensee BioMed Central Ltd. 2013
Published: 7 November 2013
T-cells have evolved the unique ability to discriminate "self" from "non-self" with high sensitivity and selectivity. However, tissue-specific autoimmunity, tolerance or eradication of cancer does not fit into the self/non-self paradigm because the T-cell responses in these situations are most often directed to non-mutated self-proteins. To determine the TCR affinity threshold defining the optimal balance between effective antitumor activity and autoimmunity in vivo, we used a novel self-antigen system comprised of seven human melanoma gp100209-217-specific TCRs spanning physiological affinities (1 to 100 μM). We found that in vitro and in vivo T cell responses are determined by TCR affinity. 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. Our results suggest a relatively low affinity threshold is necessary for the immune system to avoid self-damage given the close relationship between antitumor activity and autoimmunity. This, in turn, indicates that treatment strategies focusing on TCRs in the intermediate affinity range (KD ~10 μM) or targeting or targeting shared tumor antigens would dampen the potential for autoimmunity during adoptive T cell therapy for the treatment of cancer.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.