Faculty Opinions recommendation of 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 Abstract 1820 Poster Board I-846 T cells contribute to the immunomodulatory control of the tumor in patients with monoclonal gammopathies. We previously found that CD3+CD8+CD57+TCRVβ+restricted cytotoxic T cell expansions were present in 48% of patients with multiple myeloma (n=221) and conferred a significant favorable prognosis. We now report the presence of these expansions in 70% of patients with Waldenstrom's Macroglobulinaemia (WM) (n=20) with a wide spectrum of the TCRVβ repertoire represented. Previous nucleoside analogue (NA) therapy, known to be associated with an increased incidence of transformation to aggressive lymphoma, significantly influenced the presence of TCRVβ expansions (χ2=11.6; p<0.001) as 5 of the 6 patients without and only 1 of the 14 patients with TCRVβ expansions had received NA. Clonality of CD3+CD8+CD57+TCRVβ-restricted cytotoxic T cells was confirmed by determining the size of the TCRVβ chain CDR3 region and by direct sequencing. We identified differential gene expression by using microarray analysis (Affymetrix GeneChip Human Genome U133 plus 2.0 Arrays) and confirmed the expression of selected genes by real-time qPCR and flow cytometry. Data was analysed by paired moderated t-test and then Gene Set Enrichment Analysis (GSEA) for pathway analysis. Clonal T cells not only had upregulated genes from cytotoxic pathways (granzyme B, perforin and FGFBP2) but also genes which suppress apoptosis, proliferation, cell cycle G1/S transition arrest and T cell activation (RAS, CSK and TOB pathways) indicating anergy which was validated by CFSE tracking of proliferation after antiCD3+antiCD28 stimulation. The current studies provide further evidence for the persistence and relevance of clonal T cells in monoclonal gammopathies. Disclosures No relevant conflicts of interest to declare.

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Primary Therapy of Waldenström Macroglobulinemia With Nucleoside Analogue–Based Therapy

Clinical Lymphoma Myeloma & Leukemia ◽

10.1016/j.clml.2013.02.009 ◽

2013 ◽

Vol 13 (2) ◽

pp. 227-230 ◽

Cited By ~ 3

Author(s):

Laetitia Souchet-Compain ◽

Stéphanie Nguyen ◽

Sylvain Choquet ◽

Véronique Leblond

Keyword(s):

Nucleoside Analogue ◽

Primary Therapy ◽

Waldenström Macroglobulinemia ◽

Waldenstrom Macroglobulinemia

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Clonal expansions of cytotoxic T cells exist in the blood of patients with Waldenström macroglobulinemia but exhibit anergic properties and are eliminated by nucleoside analogue therapy

Blood ◽

10.1182/blood-2009-10-246991 ◽

2010 ◽

Vol 115 (17) ◽

pp. 3580-3588 ◽

Cited By ~ 24

Author(s):

Jia Li ◽

Daniel M.-Y. Sze ◽

Ross D. Brown ◽

Mark J. Cowley ◽

Warren Kaplan ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Direct Sequencing ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Aggressive Lymphoma ◽

Cytotoxic T Cell ◽

Size Analysis ◽

Waldenström Macroglobulinemia ◽

Waldenstrom Macroglobulinemia

AbstractT cells contribute to host-tumor interactions in patients with monoclonal gammopathies. Expansions of CD8+CD57+ T-cell receptor Vβ–positive (TCRVβ+)–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 TCRVβ 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 TCRVβ expansions (χ2 = 11.6; P < .001), as 83% of patients without (n = 6) and only 7% with (n = 14) TCRVβ expansions had received NA. Clonality of CD3+CD8+CD57+TCRVβ+-restricted CTLs was confirmed by TCRVβ CDR3 size analysis and direct sequencing. The differential expression of CD3+CD8+CD57+TCRVβ+ 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.

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