ABSTRACT
T cells express multiple integrin molecules. The significance of signaling through these molecules on acquisition of T-cell effector functions and memory formation capacity remains largely unknown. Moreover, the impact of stimulation through these signals on the generation of T cells for adoptive immunotherapy has not been elucidated. In this study, using a recombinant fragment of fibronectin, CH-296, we demonstrated that stimulation via very late Ag (VLA)-4 and VLA-5 in human and BALB/c mouse CD8(+) T cells, in combination with TCR stimulation, enhances effector multifunctionality and in vivo memory formation. Using TCR-transgenic mouse-derived CD8(+) T cells expressing TCR specific for the syngeneic CMS5 fibrosarcoma-derived tumor Ag, we showed that stimulation by CH-296 improved the ability of tumor-specific CD8(+) T cells to inhibit CMS5 tumor growth when adoptively transferred into hosts with progressing tumors. Improved antitumor effects were associated with decreased infiltration of Foxp3(+) CD4(+) Treg cells in tumors. These results suggest that stimulation via VLA-4 and VLA-5 modulates the qualities of effector T cells and could potentially increase the efficacy of adoptive therapy against cancer.
Subject(s)
Antigens, Neoplasm/immunology , Fibrosarcoma/immunology , Immunologic Memory , Integrin alpha4beta1/immunology , Integrin alpha5beta1/immunology , Adoptive Transfer , Animals , Antigens, Neoplasm/genetics , CD8-Positive T-Lymphocytes , Cell Line, Tumor , Female , Fibrosarcoma/genetics , Fibrosarcoma/pathology , Fibrosarcoma/therapy , Humans , Integrin alpha4beta1/genetics , Integrin alpha5beta1/genetics , Mice , Mice, Inbred BALB C , Mice, Transgenic , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/pathologyABSTRACT
We describe the total synthesis and structural determination of (+)-akaterpin (1), an inhibitor of phosphatidylinositol-specific phospholipase C (PI-PLC). The key features of the synthetic strategy include the resolution of ß,γ-unsaturated ketone (±)-2a with chiral sulfoximine 6. The absolute stereochemistry was determined by comparison of the specific optical rotation data of (+)-1 and (-)-1 with that of natural akaterpin.
Subject(s)
Enzyme Inhibitors/chemistry , Triterpenes/chemistry , Enzyme Inhibitors/chemical synthesis , Ketones/chemistry , Molecular Conformation , Phosphoinositide Phospholipase C/antagonists & inhibitors , Phosphoinositide Phospholipase C/metabolism , Stereoisomerism , Triterpenes/chemical synthesisABSTRACT
The pT classification of the 8th American Joint Committee on Cancer (AJCC) for distal cholangiocarcinoma (DCC) is classified according to depth of invasion (DOI), which is the distance from the basal lamina to the most deeply advanced tumor cells. The Nagoya group proposed a new T classification for DCC based on invasive tumor thickness (ITT), which is the maximal vertical distance of the invasive cancer component (the ITT grade). In this study, we aimed to validate the ITT grade for the next pT classification of DCC in 110 patients. ITT could be measured in all patients, but DOI could only be measured in 62 (56%) patients. According to ITT grade, patients were classified into grades A to D, as follows: grade A, ITT <1 mm (n=9); grade B, ITT 1 mm or more but <5 mm (n=35); grade C, ITT 5 mm or more but <10 mm (n=40); and grade D, ITT 10 mm or greater (n=26). The median overall survival times in patients with ITT grades A, B, C, and D were 12.8, 5.7, 3.7, and 2.0 years, respectively. ITT grade could discriminate postoperative survivals between grades. On multivariate analysis, ITT grade, regional lymph node metastasis, and distant metastasis were selected as independent prognostic factors. In summary, our results showed that ITT grade was a suitable alternative to DOI for pT classification in the next edition of the AJCC for DCC.