T-cell receptor affinity and avidity defines antitumor response and autoimmunity in T-cell immunotherapy

Shi Zhong, Karolina Malecek, Laura A. Johnson, Zhiya Yu, Eleazar Vega Saenz De Miera, Farbod Darvishian, Katelyn McGary, Kevin Huang, Josh Boyer, Emily Corse, Yongzhao Shao, Steven A. Rosenberg, Nicholas P. Restifo, Iman Osman, Michelle Krogsgaard

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6973-6978
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number17
DOIs
StatePublished - Apr 23 2013

Keywords

  • Adoptive cell transfer
  • Kinetic threshold
  • Ocular autoimmunity
  • Tumor immunity

ASJC Scopus subject areas

  • General

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