Abstract

Introduction: Thymus and activation-regulated chemokine (TARC/CCL17) and macrophage derived chemokine (MDC/CCL22) are specific ligands of CC chemokine receptor 4 (CCR4). We have previously reported that tumor cells obtained from a large majority of patients with adult T-cell leukemia/lymphoma (ATLL) express CCR4 and that the extent of CCR4 expression is significantly associated with unfavorable prognosis and with skin involvement. We also reveal TARC/CCL17 and MDC/CCL22 secreted by tumor cells create a favorable environment for tumor escape from host immune defense withattract CCR4+ regulatory T cells to the tumor. Collectively, it is assumed that the interactions between CCR4 and its ligands play an important role for pathogenesis of ATLL. The goal of the present study was to clarify the clinical roles of individual CCR4 ligands in ATLL patients.

Material and Method: We compared the serum levels of CCR4 ligands (TARC/CCL17 and MDC/CCL22) and helper T-cell associated cytokines (IFN-g, TNF-a, IL-2, IL-4, IL- 5, IL-6, IL-10), in 103 ATLL patients, 40 asymptomatic HTLV-1 carriers, and 50 healthy adult volunteers. We also analyzed the associations between the serum concentration of individual CCR4 ligands and the clinical characteristics such as survival time among the ATLL patients.

Result: Serum levels of TARC/CCL17 and MDC/CCL22 were significantly lower both in ATLL patients and asymptomatic HTLV-1 carriers than in healthy controls. The overall survivals were significantly shorter in ATLL patients with a high TARC/CCL17 level than in those with a low TARC/CCL17 level. Univariate cox proportional hazard analysis identified the 12 unfavorable prognostic factors including a high TARC/CCL17 level as well as a high IL-5 level, a high IL-6 level, and a high IL-10 level(Table). Multivariate analysis confirmed that a high TARC/CCL17 level was an independent and significant unfavorable prognostic factor among the ATLL patients (Table). Although a high MDC/CCL22 level was significantly associated with a high TARC/CCL17 level, serum MDC/CCL22 levels did not have prognostic significance in ATLL patients.

Conclusion: Measurement of serum TARC/CCL17 levels is useful for predicting the prognosis and for determining a suitable treatment strategy for ATLL patients.

Prognostic factors affecting overall survival in all ATLL patients. (n=103) 
Variable Unfavorable Unlvarlate Multivariate 
  Hazard ratio (95%*CI P value Hazard ratio (95%*CI) P value 
*CI, confidence Interval 
TARC/CCL17 > 285 pg/mL 1.638 (1.022–2 626) .0405 1.814 (1.109–2.969) .0177 
IL-5 > 1.7 pg/mL 2.307 (1.357–3.922) .0020 1.767 (1.008–3.096) .0468 
IL-6 > 0.7 pg/mL 1.956 (1.183–3.233) .0089 -  
IL-10 > 2.6 pg/mL 2.192 (1.254–3.830) .0059 -  
Clinical subtype Acute, lymphoma 3.539(1.851–6.767) .0001 -  
PS 2–4 2 187 (1.372–3.488) .0010 -  
B symptoms Present 2.104 (1.279–3.461) .0034 1,729 (1.040–2.872) .0346 
Hemoglobin < 100 g/dL 1.923 (1.030–3.592) .0401 -  
Albumin < 3.0 g/dL 1.854(1.029–3.338) .0397 -  
LDH > 2N 2.683(1.683–4.279) <.0001 1.876(1.086–3.242) .0241 
sIL-2R > 10,000 U/mL 3.232(1.896–5.507) <.0001 1.956(1.024–3.738) .0423 
Extranodal involvement ≥ 2 2.152 (1.352–3.426) .0012 -  
Prognostic factors affecting overall survival in all ATLL patients. (n=103) 
Variable Unfavorable Unlvarlate Multivariate 
  Hazard ratio (95%*CI P value Hazard ratio (95%*CI) P value 
*CI, confidence Interval 
TARC/CCL17 > 285 pg/mL 1.638 (1.022–2 626) .0405 1.814 (1.109–2.969) .0177 
IL-5 > 1.7 pg/mL 2.307 (1.357–3.922) .0020 1.767 (1.008–3.096) .0468 
IL-6 > 0.7 pg/mL 1.956 (1.183–3.233) .0089 -  
IL-10 > 2.6 pg/mL 2.192 (1.254–3.830) .0059 -  
Clinical subtype Acute, lymphoma 3.539(1.851–6.767) .0001 -  
PS 2–4 2 187 (1.372–3.488) .0010 -  
B symptoms Present 2.104 (1.279–3.461) .0034 1,729 (1.040–2.872) .0346 
Hemoglobin < 100 g/dL 1.923 (1.030–3.592) .0401 -  
Albumin < 3.0 g/dL 1.854(1.029–3.338) .0397 -  
LDH > 2N 2.683(1.683–4.279) <.0001 1.876(1.086–3.242) .0241 
sIL-2R > 10,000 U/mL 3.232(1.896–5.507) <.0001 1.956(1.024–3.738) .0423 
Extranodal involvement ≥ 2 2.152 (1.352–3.426) .0012 -  

Disclosures: No relevant conflicts of interest to declare.

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