title: Expression profiling of TCR-engineered T cells demonstrates overexpression of multiple inhibitory receptors in persisting lymphocytes.
abstract: Despite significant progress in the development of adoptive cell-transfer therapies (ACTs) using gene-engineered T cells, little is known about the fate of cells following infusion. To address that, we performed a comparative analysis of gene expression between T-cell receptor-engineered lymphocytes persisting in the circulation 1 month after administration and the product that was infused. We observed that 156 genes related to immune function were differentially expressed, including underexpression of stimulators of lymphocyte function and overexpression of inhibitory genes in postinfusion cells. Of genes overexpressed postinfusion, the product of programmed cell death 1 (PDCD1), coinhibitory receptor PD-1, was expressed at a higher percentage in postinfusion lymphocytes than in the infusion product. This was associated with a higher sensitivity to inhibition of cytokine production by interaction with its ligand PD-L1. Coinhibitory receptor CD160 was also overexpressed in persisting cells, and its expression was associated with decreased reactivity, which surprisingly was found to be ligand-independent. These results contribute to a deeper understanding of the properties of transgenic lymphocytes used to treat human malignancies and may provide a rationale for the development of combination therapies as a method to improve ACT.
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Dr., Bethesda, MD 20892, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Abate-Daga
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Hanada
authors.forename: Jeremy L
authors.initials: JL
authors.lastname: Davis
authors.forename: James C
authors.initials: JC
authors.lastname: Yang
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: Richard A
authors.initials: RA
authors.lastname: Morgan
mesh_terms: D019264:Adoptive Transfer; D000328:Adult; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D058851:GPI-Linked Proteins / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005818:Genetic Engineering; D006801:Humans; D008024:Ligands; D008297:Male; D008545:Melanoma / Q000097:blood / Q000188:drug therapy; D051379:Mice; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*; D055815:Young Adult
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; C114505:CD160 protein, human; D058851:GPI-Linked Proteins; D008024:Ligands; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell; D011971:Receptors, Immunologic