adh-1-pepide and Prostatic-Neoplasms

Few patients with prostate cancer benefit from current immunotherapies. Therefore, we aimed to explore new strategies to change this paradigm.. Human tissues, cell lines and in vivo experiments were used to determine whether and how N-cadherin impacts the production of programmed death ligand-1 (PD-L1) and indole amine 2,3-dioxygenase (IDO-1) and whether N-cadherin can increase the production of effector (e)Treg cells. Then, we used PC3-bearing humanized non-obese diabetic/severe combined immunodeficiency IL2Rγnull (hNSG) mice with an intravenous injection of human CD34+ hematopoietic stem cells into the tail vein to evaluate whether the N-cadherin antagonist N-Ac-CHAVC-NH2 (designated ADH-1) could improve the therapeutic effect of tumor-infiltrating lymphocyte (TIL)-related treatment.. N-cadherin dramatically upregulated the expression of PD-L1 and IDO-1 through IFN-γ (interferongamma) signaling and increasing the production of free fatty acids that could promote the generation of eTreg cells. In preclinical experiments, immune reconstitution mediated by TILs slowed tumor growth and extended the survival time; however, this effect disappeared after immune system suppression by PD-L1, IDO-1 and eTreg cells. Furthermore, ADH-1 effectively reduced immunosuppression and enhanced TIL-related therapy.. These data show that the N-cadherin antagonist ADH-1 promotes TIL antitumor responses. This important hurdle must be overcome for tumors to respond to immunotherapy.

Topics: Animals; Antigens, CD; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Cadherins; Drug Resistance, Neoplasm; Humans; Immune Checkpoint Inhibitors; Indoleamine-Pyrrole 2,3,-Dioxygenase; Janus Kinase 1; Lymphocytes, Tumor-Infiltrating; Male; Mice, Inbred NOD; Mice, SCID; Oligopeptides; PC-3 Cells; Peptides, Cyclic; Prostatic Neoplasms; Signal Transduction; T-Lymphocytes, Regulatory; Tumor Microenvironment; Xenograft Model Antitumor Assays

The conversion from E-cadherin to N-cadherin has been observed in several human cancer types, including prostate cancer, with more homogenous expression of N-cadherin detected in high-grade prostate tumors. N-cadherin, in vitro, has been shown to promote cell mobility, migration and invasion of several cancer cell lines, indicating the possibility of N-cadherin as a molecular target of cancer therapy. Herein, we examined the potential of an N-cadherin inhibitor, ADH1, in reducing tumor angiogenesis ex vivo and delaying tumor progression in vivo. Our data demonstrate that ADH1, at the dosages evaluated, does not display either antiangiogenic activity in a rat aortic ring assay or antitumor potential in a PC3 subcutaneous xenograft tumor model. We detected cytotoxic activity in human umbilical vein endothelial cells, PC3, and Tsu-Pr1 cells, when ADH1 exposure was evaluated at 500 micromol/l or above.

Topics: alpha Catenin; Androgens; Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Aorta, Thoracic; Blotting, Western; Cadherins; Endothelial Cells; In Vitro Techniques; Male; Neoplasm Transplantation; Neovascularization, Pathologic; Oligopeptides; Peptides, Cyclic; Prostatic Neoplasms; Rats; Regional Blood Flow