title: Clonal expansions of cytotoxic T cells exist in the blood of patients with Waldenstrom macroglobulinemia but exhibit anergic properties and are eliminated by nucleoside analogue therapy.
abstract: T cells contribute to host-tumor interactions in patients with monoclonal gammopathies. Expansions of CD8(+)CD57(+) T-cell receptor Vbeta-positive (TCRVbeta(+))-restricted cytotoxic T-cell (CTL) clones are found in 48% of patients with multiple myeloma and confer a favorable prognosis. We now report that CTL clones with varying TCRVbeta repertoire are present in 70% of patients with Waldenström macroglobulinemia (WM; n = 20). Previous nucleoside analog (NA) therapy, associated with increased incidence of transformation to aggressive lymphoma, significantly influenced the presence of TCRVbeta expansions (chi(2) = 11.6; P < .001), as 83% of patients without (n = 6) and only 7% with (n = 14) TCRVbeta expansions had received NA. Clonality of CD3(+)CD8(+)CD57(+)TCRVbeta(+)-restricted CTLs was confirmed by TCRVbeta CDR3 size analysis and direct sequencing. The differential expression of CD3(+)CD8(+)CD57(+)TCRVbeta(+) cells was profiled using DNA microarrays and validated at mRNA and protein level. By gene set enrichment analysis, CTL clones expressed not only genes from cytotoxic pathways (GZMB, PRF1, FGFBP2) but also genes that suppress apoptosis, inhibit proliferation, arrest cell-cycle G1/S transition, and activate T cells (RAS, CSK, and TOB pathways). Proliferation tracking after stimulation confirmed their anergic state. Our studies demonstrate the incidence, NA sensitivity, and nature of clonal CTLs in WM and highlight mechanisms that cause anergy in these cells.
authors.affiliation: Cancer Immunology Group, Faculty of Pharmacy, University of Sydney, Sydney, Australia.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Daniel M-Y
authors.initials: DM
authors.lastname: Sze
authors.forename: Ross D
authors.initials: RD
authors.lastname: Brown
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Cowley
authors.forename: Warren
authors.initials: W
authors.lastname: Kaplan
authors.forename: Sui-Lin
authors.initials: SL
authors.lastname: Mo
authors.forename: Shihong
authors.initials: S
authors.lastname: Yang
authors.forename: Esther
authors.initials: E
authors.lastname: Aklilu
authors.forename: Karieshma
authors.initials: K
authors.lastname: Kabani
authors.forename: Yen S
authors.initials: YS
authors.lastname: Loh
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Yamagishi
authors.forename: Yuling
authors.initials: Y
authors.lastname: Chen
authors.forename: P Joy
authors.initials: PJ
authors.lastname: Ho
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Joshua
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D017635:Clonal Anergy; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D009705:Nucleosides / Q000627:therapeutic use*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008258:Waldenstrom Macroglobulinemia / Q000097:blood* / Q000188:drug therapy / Q000235:genetics / Q000276:immunology
chemical_list: D015703:Antigens, CD; D009363:Neoplasm Proteins; D009705:Nucleosides; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D016693:Receptors, Antigen, T-Cell, alpha-beta