HTLV-1 Tax-specific memory cytotoxic T lymphocytes in long-term survivors of aggressive-type adult T-cell leukemia/lymphoma

Tatsuro Jo; Kazuhiro Noguchi; Takahiro Sakai; Ritsuko Kubota-Koketsu; Sadaharu Irie; Masatoshi Matsuo; Jun Taguchi; Kuniko Abe; Kazuto Shigematsu

doi:10.1002/cam4.4689

HTLV-1 Tax-specific memory cytotoxic T lymphocytes in long-term survivors of aggressive-type adult T-cell leukemia/lymphoma

Cancer Med. 2022 Sep;11(17):3238-3250. doi: 10.1002/cam4.4689. Epub 2022 Mar 22.

Authors

Tatsuro Jo¹, Kazuhiro Noguchi², Takahiro Sakai², Ritsuko Kubota-Koketsu³, Sadaharu Irie⁴, Masatoshi Matsuo¹, Jun Taguchi¹, Kuniko Abe⁵, Kazuto Shigematsu⁵

Affiliations

¹ Department of Hematology, Japanese Red Cross Nagasaki Genbaku Hospital, Nagasaki, Japan.
² Department of Laboratory, Japanese Red Cross Nagasaki Genbaku Hospital, Nagasaki, Japan.
³ Department of Viral Infections, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
⁴ Department of Pharmacy, Japanese Red Cross Nagasaki Genbaku Hospital, Nagasaki, Japan.
⁵ Department of Pathology, Japanese Red Cross Nagasaki Genbaku Hospital, Nagasaki, Japan.

Abstract

Purpose: Adult T-cell leukemia/lymphoma (ATLL) is a relatively refractory peripheral T-cell lymphoma caused by human T-cell lymphotropic virus type 1 (HTLV-1). The objective of this study was to investigate the characteristics of long-term survivors with ATLL.

Methods: We conducted an observational study of 75 aggressive-type ATLL patients. Flow cytometry was conducted to analyze HTLV-1 Tax-specific cytotoxic T-lymphocytes (CTLs) and T-cell receptor Vβ gene repertoire.

Results: We first evaluated six long-term survivors among 37 patients who were newly diagnosed with ATLL and then treated with intensive chemotherapy without mogamulizumab, a monoclonal antibody for C-C chemokine receptor four antigen. Reversal of the CD4-to-CD8 ratio (CD4/CD8) in peripheral mononuclear cells was observed in all six patients. Three of these six patients showed reversed CD4/CD8 immediately after herpes virus infection. Four of these six patients who could be examined demonstrated long-term maintenance of HTLV-1 Tax-specific CTLs. We subsequently identified four long-term survivors among 38 patients who were newly diagnosed with ATLL and then treated with intensive chemotherapy plus mogamulizumab. All four patients showed reversed CD4/CD8, and three of the four patients contracted herpes virus infection during immunochemotherapy. Six of the total 10 patients were subjected to CTL analyses. Tax-specific CTLs were observed, and the CTLs that were almost entirely composed of memory CTLs in all patients were recorded. HTLV-1 provirus was also detected in all six patients.

Conclusions: These data suggest that Tax-specific memory CTLs probably, together with anticancer agents, eradicate ATLL cells and exhibit long-term preventive effects from relapse ATLL. Thus, the strong activation of cellular immunity, such as herpes virus infection, seems to be necessary to induce such a potent number of Tax-specific CTLs.

Keywords: Tax; adult T-cell leukemia/lymphoma; cytotoxic T-lymphocytes; herpes virus infection; human T-cell lymphotropic virus type 1.

Publication types

Observational Study

MeSH terms

Adult
Antineoplastic Agents*
Gene Products, tax / genetics
HTLV-I Infections*
Human T-lymphotropic virus 1* / genetics
Humans
Leukemia-Lymphoma, Adult T-Cell* / genetics
Lymphoma, T-Cell, Peripheral*
Survivors
T-Lymphocytes, Cytotoxic
Virus Diseases*

Substances

Antineoplastic Agents
Gene Products, tax