title: T-cell receptor affinity and avidity defines antitumor response and autoimmunity in T-cell immunotherapy.
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-generated high-affinity TCRs do not necessarily improve efficacy.
authors.affiliation: New York University Cancer Institute, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Shi
authors.initials: S
authors.lastname: Zhong
authors.forename: Karolina
authors.initials: K
authors.lastname: Malecek
authors.forename: Laura A
authors.initials: LA
authors.lastname: Johnson
authors.forename: Zhiya
authors.initials: Z
authors.lastname: Yu
authors.forename: Eleazar
authors.initials: E
authors.lastname: Vega-Saenz de Miera
authors.forename: Farbod
authors.initials: F
authors.lastname: Darvishian
authors.forename: Katelyn
authors.initials: K
authors.lastname: McGary
authors.forename: Kevin
authors.initials: K
authors.lastname: Huang
authors.forename: Josh
authors.initials: J
authors.lastname: Boyer
authors.forename: Emily
authors.initials: E
authors.lastname: Corse
authors.forename: Yongzhao
authors.initials: Y
authors.lastname: Shao
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
authors.forename: Iman
authors.initials: I
authors.lastname: Osman
authors.forename: Michelle
authors.initials: M
authors.lastname: Krogsgaard
mesh_terms: D000704:Analysis of Variance; D015551:Autoimmunity / Q000276:immunology*; D003601:Cytotoxicity Tests, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D005453:Fluorescence; D006801:Humans; D007150:Immunohistochemistry; D016219:Immunotherapy, Adoptive / Q000379:methods*; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D014161:Transduction, Genetic; D058951:gp100 Melanoma Antigen / Q000276:immunology
chemical_list: D011948:Receptors, Antigen, T-Cell; D058951:gp100 Melanoma Antigen