Myeloid DNAX activation protein 12 (DAP12)-associating lectin-1 (MDL-1), also known as C-type lectin domain family 5, member A, is a type II transmembrane protein belonging to the C-type lectin family and associates with DAP12 (also called KARAP or TYROBP). It has been reported that two isoforms of MDL-1-long form (MDL-1L) and short form (MDL-1S)-exist in mice. Previously, we observed the marked induction of MDL-1 mRNA expression during the pulmonary mycobacterial infection in mice. The data suggested that the MDL-1-expressing cells were involved in immune responses against mycobacterial infection; however, little is known about the function of MDL-1 as yet. In this study, we demonstrated the significant protein expression of MDL-1L and MDL-1S in mouse neutrophils and macrophages. MDL-1L was highly glycosylated by N-linked glycan and sialic acid. Interestingly, the expression pattern of MDL-1 was different between neutrophils and macrophages. MDL-1 expression was notably induced during the differentiation of the mouse myeloid cell line 32Dcl3 into neutrophils. Additionally, we observed that MDL-1 stimulation induced a significant amount of RANTES and macrophage-derived chemokine production in 32Dcl3 cells in cooperation with signaling through TLR. MDL-1 stimulation also up-regulated CD11b expression and maintained cell survival. Our findings indicate that MDL-1, therefore, plays an important role in immune defense as a result of an innate immunity, which involves neutrophils and macrophages.

EBV-encoded latent membrane protein 1 (LMP1) has oncogenic potential and is expressed in many EBV-associated malignancies. Although LMP1 is regarded as a potential tumor-associated antigen for immunotherapy and several LMP1-specific MHC class I-restricted CTL epitopes have been reported, little is known regarding MHC class II-restricted CD4 helper T-lymphocyte (HTL) epitopes for LMP1. The goal of the present studies was to determine whether MHC class IIrestricted CD4 T-cell responses could be induced against the LMP1 antigen and to evaluate the antitumor effect of these responses. We have combined the use of a predictive MHC class II binding peptide algorithm with in vitro vaccination of CD4 T cells using candidate peptides to identify naturally processed epitopes derived from LMP1 that elicit immune responses against EBV-expressing tumor cells. Peptide LMP1 [159][160][161][162][163][164][165][166][167][168][169][170][171][172][173][174][175] was effective in inducing HTL responses that were restricted by HLA-DR9, HLA-DR53, or HLA-DR15, indicating that this peptide behaves as a promiscuous T-cell epitope. Moreover, LMP1 159-175 -reactive HTL clones directly recognized EBV lymphoblastoid B cells, EBV-infected natural killer (NK)/T-lymphoma cells and naturally processed antigen in the form of LMP1+ tumor cell lysates presented by autologous dendritic cells. Because the newly identified epitope LMP1 159-175 overlaps with an HLA-A2-restricted CTL epitope (LMP1 [159][160][161][162][163][164][165][166][167] ), this peptide might have the ability to induce simultaneous CTL and HTL responses against LMP1. Overall, our data should be relevant for the design and optimization of T-cell epitope-based immunotherapy against various EBVassociated malignancies, including NK/T cell lymphomas. [Cancer Res 2008;68(3):901-8]

Results show that STEAP helper T-lymphocyte epitopes could be used to optimize T-cell based immunotherapy against STEAP expressing renal cell and bladder cancer.

The six-transmembrane epithelial antigen of prostate (STEAP) protein is an attractive candidate for T cell-based immunotherapy because it is overexpressed in prostate cancer and various other tumor types. Several peptide epitopes capable of stimulating CTLs that killed STEAP-expressing tumor cells have been described. Our goal was the identification of helper T lymphocyte (HTL) epitopes of STEAP for the optimization of T cell-based immunotherapies against STEAP-expressing malignancies. Candidate HTL epitopes for STEAP were predicted using in silico algorithms for HLA class II-binding peptides and were tested for their ability to elicit HTL responses by in vitro peptide vaccination of CD4 T lymphocytes from healthy individuals and prostate cancer patients. Two peptides ) were effective in stimulating in vitro antitumor HTL responses in both normal individuals and prostate cancer patients. Notably, both STEAP HTL peptides behaved as promiscuous T-cell epitopes because they stimulated T cells in the context of more than one MHC class II allele. These newly described STEAP HTL epitopes could be of value for the design and optimization of T cell-based immunotherapy against STEAP-expressing tumors. [Cancer Res 2007;67(11):5498-504]

The present study shows a relatively good long-term persistence rate with mirabegron in overactive bladder patients, notwithstanding the retrospective study in an academic hospital. The combined treatment with antimuscarinics could result in a good persistence rate with mirabegron.