Zoledronate-activated Vγ9γδ T cell-based immunotherapy is feasible and restores the impairment of γδ T cells in patients with solid tumors.

Gamma/delta (γδ) T cells play a role in innate immunity and exhibit cytotoxicity toward a large range of tumor types. Recent studies have shown that aminobisphosphonates may be applied to a culture in which a large number of γδ T cells are proliferated ex vivo. We carried out a clinical study of 25 patients with various solid tumors to determine further the safety, immunologic effect and feasibility of zoledronate-activated Vγ9γδ T cell-based immunotherapy. No severe toxicity was observed. In the cells used for the first treatment, the total cell number, frequency and number of CD3(+) Vγ9(+) γδ T cells were 409 ± 284 × 10(7) cells, 56 ± 33% and 255 ± 242 × 10(7) cells, respectively. Aminobisphosphonate therapy or chemotherapy resulted in the suppression of CD3(+) Vγ9(+) γδ T-cell proliferation. The numbers of CD3(+) T cells, CD3(+) Vγ9(+) γδ T cells and CD27(-) CD45RA(-) Vγ9(+) subsets in peripheral blood were significantly lower in patients than in healthy subjects (P < 0.05). From such an impaired immunologic condition, the numbers and frequencies of CD3(+) Vγ9(+) γδ T cells and CD27(-) CD45RA(-) subsets significantly increased in patients treated with this immunotherapy. Zoledronate-activated Vγ9γδ T cell-based immunotherapy that restores the number of Vγ9γδ T cells in cancer patients may provide another mode of adoptive immunotherapy.

The therapeutic potential of immuno-cell therapy of cancer in combination with aminobisphosphonates.

Many university hospitals and cancer centers in Japan have actively investigated the use of autologous activated lymphocyte therapy (ALT). However its therapeutic efficacy was found to be quite limited. The efficacy of aminobisphosphonates (aBPs) has been shown for osteolytic bone disease. aBPs could activate and induce the proliferation of gamma/delta (gamma/delta) T-cells. The application of aBPs to ALT in vivo or ex vivo may be beneficial. A brief overview of aBPs and gamma/delta T-cells is provided, together with some preliminary results and discussion of the therapeutic potential of ALT in combination with aBPs.

Detection of anti-HLA-F antibodies in sera from cancer patients.

BACKGROUND: We previously reported that a Q5 gene product (Q5 antigen) on the surface of tumor cells caused humoral immune reaction in syngeneic tumor-bearing mice. Transcripts of the Q5 gene were observed in various tumor cells. The human counterpart of the Q5 gene has not been clarified yet. MATERIALS AND METHODS: Transcripts of human class Ib genes in various human tumor cell lines were analyzed by the RT-PCR method. Whether anti-HLA-F antibodies were present in sera from cancer patients was investigated through Western blotting with recombinant HLA-F as an antigen. RESULTS: Transcripts of the HLA-F gene were produced by various tumor cell lines. In addition, anti-HLA-F IgG was present in the sera derived from various types of cancer patients (26 positives / 42 tested), but not in the sera derived from healthy donors (0 / 20). CONCLUSION: Anti-HLA-F antibodies should be further investigated as possible diagnostic tumor markers.

Impaired and imbalanced cellular immunological status assessed in advanced cancer patients and restoration of the T cell immune status by adoptive T-cell immunotherapy.

Recent progress has been made in understanding the mechanisms of antitumor immune responses, which may further clarify the immune status of cancer patients. In this study, we performed a detailed evaluation of the immunological status of 47 patients with advanced solid cancer, who had received no immunosuppressive treatment, and compared the results with 32 healthy subjects. Flow-cytometry data for peripheral blood were obtained using 19 monoclonal antibodies against various cell surface and intracellular molecules. Absolute numbers of T cells, several T cell subsets, B cells, and NK cells were significantly decreased in patients compared with healthy subjects. The percentage of CD27(+)CD45RA(+) T cells was lower and that of CD27(-)CD45RA(-) T cells was higher in patients compared with controls. Regulatory and type 2 helper T cells were elevated in patients relative to healthy subjects. The percentage of perforin(+) NK cells was significantly lower in patients than in controls. These results suggest a dysfunctional anti-tumor immune response in cancer patients. Furthermore, peripheral blood from 26 of 47 cancer patients was analyzed after adoptive T cell immunotherapy (ATI). ATI increased the number of T cell subsets, but not B and NK cells. The number and percentage of regulatory T cells decreased significantly. These results suggest that ATI can restore impaired and imbalanced T cell immune status.

Complex formation of CD23/surface immunoglobulin and CD23/CD81/MHC class II on an EBV-transformed human B cell line and inferable role of tetraspanin.

CD23, a low-affinity IgE receptor, is a type II transmembrane protein having a C-type lectin domain and it associates noncovalently with MHC class II on B cells. The results of our immunoprecipitation analysis suggest that CD23 co-exists with at least two additional molecules, surface immunoglobulin (sIg) and CD81 (and/or CD9), on the cell surface of L-KT9 cells (an Epstein-Barr virus (EBV)-transformed human B cell line). When both CD23 and sIg molecules were stimulated simultaneously by the corresponding antibodies, a large increase in CD81 in the immunoprecipitation was observed as compared with the case of stimulation by only one antibody. Simultaneous stimulation by anti-CD23 and anti-Ig may mimic the situation of B cells stimulated by an antigen/IgE complex. In addition, a large increase in MHC class II in the immunoprecipitation was also observed by cross-linking of CD23 with anti-CD23 and its second antibody as compared with the case of stimulation by anti-CD23 alone. The cross-linking of CD23 with anti-CD23 and its antibody may mimic the situation of B cells stimulated by an IgE/antigen/IgE complex. Therefore, the complex formation among CD23, sIg, MHC class II, and CD81 on the cell surface of L-KT9 cells by the antigen/IgE or IgE/antigen/IgE complex is most likely to be closely related to B cell regulatory events by signaling through sIg or MHC class II. Tetraspanins such as CD81 and CD9 are thought to be involved in the formation and the preservation of various different membrane complexes consisting of several functional proteins.