Abstract
There is growing evidence that CD8+ cytotoxic T lymphocyte (CTL) responses can contribute to long-term remission of many malignancies. The etiological agent of adult T-cell leukemia/lymphoma (ATL), human T lymphotropic virus type-1 (HTLV-1), contains highly immunogenic CTL epitopes, but ATL patients typically have low frequencies of cytokine-producing HTLV-1-specific CD8+ cells in the circulation. It remains unclear whether patients with ATL possess CTLs that can kill the malignant HTLV-1 infected clone. Here we used flow cytometric staining of TCRVβ and cell adhesion molecule-1 (CADM1) to identify monoclonal populations of HTLV-1-infected T cells in the peripheral blood of patients with ATL. Thus, we quantified the rate of CD8+-mediated killing of the putative malignant clone in ex vivo blood samples. We observed that CD8+ cells from ATL patients were unable to lyse autologous ATL clones when tested directly ex vivo. However, short in vitro culture restored the ability of CD8+ cells to kill ex vivo ATL clones in some donors. The capacity of CD8+ cells to lyse HTLV-1 infected cells which expressed the viral sense strand gene products was significantly enhanced after in vitro culture, and donors with an ATL clone that expressed the HTLV-1 Tax gene were most likely to make a detectable lytic CD8+ response to the ATL cells. We conclude that some patients with ATL possess functional tumour-specific CTLs which could be exploited to contribute to control of the disease.
Highlights
CD8+ Cell Killing of adult T-cell leukemia/lymphoma (ATL) Clones Quantified by TCRVβ Flow Cytometry
Adult T cell leukemia/lymphoma is a mature T cell malignancy caused by the retrovirus human T lymphotropic virus-1 (HTLV-1)
The frequency distributions of TCRVβ subunits in cell adhesion molecule-1 (CADM1)+ and CADM1− T cells were ascertained by dividing live CD3+ cells into 50 possible groups on the basis of TCRVβ staining
Summary
Adult T cell leukemia/lymphoma is a mature T cell malignancy caused by the retrovirus human T lymphotropic virus-1 (HTLV-1). Four clinical subtypes exist: acute, lymphoma, chronic and smouldering, which range from highly aggressive to indolent in their clinical course [1,2]. Antiviral drugs (zidovudine and interferon alpha, AZT/IFN)[4,5,6,7] and molecular targeted therapy (anti-CCR4, Mogamulizumab) [8,9,10] have shown promising results, especially in chronic ATL, but their efficacy in the lymphoma and acute subtypes is limited. Malignant cells in ATL are HTLV-1-infected clones: in 91% of ATL cases a single dominant proviral integration site makes up over 35% of the proviral load[15], circulating alongside subdominant populations of polyclonal infected and uninfected T cells. The genomic integration site influences clonal proliferation and proviral gene expression[16], it does not appear to explain clonal dominance in most cases of ATL[15]. Spontaneous mutations in the T cell receptor (TCR)/NF-kB[17], CCR4[18], p53 [19] and, Notch-1[20] signalling pathways are frequently observed in malignant clones
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