Research Article: T Cell Receptor Vβ Staining Identifies the Malignant Clone in Adult T cell Leukemia and Reveals Killing of Leukemia Cells by Autologous CD8+ T cells

Date Published: November 28, 2016

Publisher: Public Library of Science

Author(s): Aileen G. Rowan, Aviva Witkover, Anat Melamed, Yuetsu Tanaka, Lucy B. M. Cook, Paul Fields, Graham P. Taylor, Charles R. M. Bangham, Ronald C. Desrosiers.

http://doi.org/10.1371/journal.ppat.1006030

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.

Partial Text

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]. Advances in chemotherapy protocols have contributed only a modest increase in overall survival of aggressive subtypes, and few patients receive potentially curative allogeneic hematopoietic stem cell transplantation (HSCT)[3]. Antiviral drugs (zidovudine and interferon alpha, AZT/IFN)[4–7] and molecular targeted therapy (anti-CCR4, Mogamulizumab)[8–10] have shown promising results, especially in chronic ATL, but their efficacy in the lymphoma and acute subtypes is limited. There is an urgent need for new therapies and strategies to consolidate existing treatments.

An array of novel anti-cancer immune therapies are currently in clinical trials, which potentiate existing immune responses, and induce tumour-specific immunity by vaccination, or infusion of engineered tumour-specific T cells. Might these approaches be effective in ATL?

 

Source:

http://doi.org/10.1371/journal.ppat.1006030

 

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