title: Adoptive T cell therapy promotes the emergence of genomically altered tumor escape variants.
abstract: Adoptive T cell therapy has been proven effective against melanoma in mice and humans. However, because most responses are incomplete or transient, cures remain rare. To maximize the efficacy of this therapy, it will be essential to gain a better understanding of the processes which result in tumor relapse. We studied these processes using B16ova murine melanoma and adoptive transfer of OT-I T cells. Transfer of T cells as a single therapy provided a significant survival benefit for mice with established subcutaneous tumors. However, tumors which initially regressed often recurred. By analyzing tumors which emerged in the presence of a potent OT-I response, we identified a novel tumor escape mechanism in which tumor cells evaded T cell pressure by undergoing major genomic changes involving loss of the gene encoding the target tumor antigen. Furthermore, we show that these in vivo processes can be recapitulated in vitro using T cell/tumor cell co-cultures. A single round of in vitro co-culture led to significant loss of the ova gene and a tumor cell population with rapidly induced and diverse karyotypic changes. Although these current studies focus on the model OVA antigen, the finding that T cells can directly promote genomic instability has important implications for the development of adoptive T cell therapies.
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Kaluza
authors.forename: Jill M
authors.initials: JM
authors.lastname: Thompson
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kottke
authors.forename: Heather C
authors.initials: HC
authors.lastname: Flynn Gilmer
authors.forename: Darlene L
authors.initials: DL
authors.lastname: Knutson
authors.forename: Richard G
authors.initials: RG
authors.lastname: Vile
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001483:Base Sequence; D018920:Coculture Techniques; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D042822:Genomic Instability; D023281:Genomics; D017404:In Situ Hybridization, Fluorescence; D008213:Lymphocyte Activation; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D060888:Real-Time Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D019139:Tumor Escape / Q000235:genetics*
chemical_list: D017931:DNA Primers