Journal article
T-cell receptor affinity and avidity defines antitumor response and autoimmunity in T-cell immunotherapy
Proceedings of the National Academy of Sciences - PNAS, Vol.110(17), pp.6973-6978
04/23/2013
DOI: 10.1073/pnas.1221609110
PMCID: PMC3991230
PMID: 23576742
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
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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-generated high-affinity TCRs do not necessarily improve efficacy.
Details
- Title: Subtitle
- T-cell receptor affinity and avidity defines antitumor response and autoimmunity in T-cell immunotherapy
- Creators
- Shi Zhong - New York University Cancer InstituteKarolina Malecek - New York UniversityLaura A. Johnson - National Cancer InstituteZhiya Yu - National Cancer InstituteEleazar Vega-Saenz de Miera - Ronald O. Perelman Department of Dermatology, Interdisciplinary Melanoma Cooperative GroupFarbod Darvishian - New York UniversityKatelyn McGary - New York UniversityKevin Huang - New York UniversityJosh Boyer - New York UniversityEmily Corse - Memorial Sloan Kettering Cancer CenterYongzhao Shao - New York UniversitySteven A. Rosenberg - National Institutes of HealthNicholas P. Restifo - National Institutes of HealthIman Osman - New York UniversityMichelle Krogsgaard - New York University
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.110(17), pp.6973-6978
- DOI
- 10.1073/pnas.1221609110
- PMID
- 23576742
- PMCID
- PMC3991230
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Alternative title
- TCR affinity for adoptive cell therapy
- Language
- English
- Date published
- 04/23/2013
- Academic Unit
- Surgery
- Record Identifier
- 9984502460102771
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