CD4+ Treg cells expressing the transcription factor FOXP3 (forkhead box P3) are abundant in tumor tissues and appear to hinder the induction of effective antitumor immunity. A substantial number of T cells, including Treg cells, in tumor tissues and peripheral blood express C-C chemokine receptor 4 (CCR4). Here we show that CCR4 was specifically expressed by a subset of terminally differentiated and most suppressive CD45RA + T-cell responses in an adult T-cell leukemia-lymphoma patient whose leukemic cells expressed NY-ESO-1. Collectively, these findings indicate that anti-CCR4 mAb treatment is instrumental for evoking and augmenting antitumor immunity in cancer patients by selectively depleting eTreg cells.cancer immunotherapy | immunomodulation

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By the use of sucrose gelatin veronal buffer (SGVB), a simple screening test was developed by us to detect sera with low complement activity, including C9-deficient sera. Using this screening test, we were able to identify sera with low complement activity including C9-deficient sera among a large number of samples. Further examinations, estimation of the protein concentration of C9, C4, C3, etc., enabled classification of serum with low complement activity into C9-deficient serum, serum deficient in the other components, and serum with low complement activity caused by non-specific activation of complement through the classical pathway by low temperature in vitro. Among 145,640 sera from Osaka donors, 138 sera were found to be deficient in C9 by these methods. The whole complement activity (CH50) of the 138 sera was 13.1 +/- 3.0 U/ml. The C9 protein in these sera was undetectable, not only by the single radial immunodiffusion method, but also by the sensitive ELISA method. C9 activities in these sera were less than 0.1% of the level in pooled normal human serum. These findings and the family studies revealed that 138 blood donors unquestionably had a hereditary C9 deficiency. The incidence of C9 deficiency among Osaka donors was calculated to be 0.095%.

Levels of the membrane complement regulatory proteins, C3b/C4b receptor (CR1, CD35), membrane cofactor protein (MCP, CD46), and decay-accelerating factor (DAF, CD55), expressed on cells from patients with haematological malignancies and normal subjects were assessed by flowcytometry using the respective monoclonal antibodies (mAbs). All myeloid and most lymphoid leukaemia samples tested were CR1-negative: two of the 42 leukaemia samples expressed minute amounts of CR1. Lack of CR1 in leukaemia cells was confirmed with two mAbs raised against CR1, 31R, and 243R, which recognized different epitopes and induced different degrees of CR1-mediated fluorescent shift on flow-cytometry in granulocytes and erythrocytes. MCP was increased in most chronic myelogenous leukaemia (CML) and chronic lymphocytic leukaemia (CLL), and was also increased in majority of acute nonlymphocytic leukaemia (ANLL), acute lymphocytic leukaemia (ALL) and non-Hodgkin's lymphoma (NHL). Levels of DAF were also high in CML and CLL, and were variable in other types of leukaemia: some were DAF-negative while others expressed extremely high levels of DAF. In CML patients, the high level of MCP and the lack of CR1 were normalized after medical treatment. These results are in agreement with the data obtained with human leukaemia cell lines, and support the hypothesis that CR1 is essentially a differentiated cell antigen and that a high level of MCP reflects some malignant transformation or an immature stage in blood cells.

IntroductionAdult T-cell leukemia/lymphoma (ATLL) is a distinct hematologic malignancy caused by human T-lymphotropic virus type 1 (HTLV-1). 1,2 HTLV-1 is endemic in southwestern Japan, Africa, South America, and the Caribbean Islands, and approximately 20 million people worldwide are infected. 3 A total of 5% of the infected persons develop ATLL after a long latency period. 2 ATLL cells are CD4-positive; and the majority, if not all, of them express the transcription factor FoxP3 (Forkhead Box P3), CD25, CTLA-4, and CCR4 (CC chemokine receptor 4), and are functionally immunosuppressive, thus phenotypically and functionally resembling naturally occurring regulatory T cells (Tregs). [3][4][5][6][7][8][9] Because of its immunosuppressive property and resistance to conventional chemotherapy, aggressive ATLL has a poor prognosis with a mean survival time of less than 1 year. 2,8 A recent phase 3 trial of a dose-intensified multidrug chemotherapy for untreated ATLL patients (acute, lymphoma, and unfavorable chronic types) showed a median progression-free and overall survival of only 7.0 and 12.7 months, respectively. 10 This and other reports indicate that chemotherapy alone is of limited success for ATLL and mostly fails to cure the disease. 10,11 Allogeneic hematopoietic stem cell transplantation has been introduced over the past decade as a potential therapy for ATLL with a long-term remission in only a small fraction of patients who are young, well controlled in disease progression, and have an appropriate stem cell source. 12 More effective strategies to treat ATLL are therefore required.Several HTLV-1 components have been explored as targets for immunotherapy of ATLL. HTLV-1 Tax, which is crucial for ATLL oncogenesis, has generally been considered to be a main target of the host's cellular immune responses. Yet, the frequency of Tax expression in HTLV-1 infected cells reduces in the course of disease progression, and Tax transcripts are detected only in approximately 40% of the established ATLL cases, 13 thus limiting Tax-targeted immunotherapy to a subset of patients. HBZ (HTLV-1 bZIP factor), another HTLV-1 component, which contains an N-terminal transcriptional activation domain and a leucine zipper motif at its C-terminal, also plays an important role in the proliferation of ATLL cells and is detectable in almost all ATLL cases. 2 However, CD8 ϩ T cells specific for HBZ could only recognize peptide-pulsed target cells but not ATLL cells themselves. 14 Furthermore, HTLV-1 is transmitted mainly from mothers to infants through breast milk, and such vertical infection in early life may induce tolerance to the virus and result in insufficient HTLV-1-specific T-cell responses. 15,16 For these reasons, targeting the HTLV-1 components alone may be insufficient for successful immunotherapy of ATLL, necessitating identification of novel tumor-associated target antigens for the immunotherapy.The expression of cancer/testis (CT) antigens, of which more than 100 have been identified so far, is normally limited to human ...