tretinoin and Carcinoma--Lewis-Lung

CD1d-restricted natural killer T (NKT) cells are a potential therapeutic target for cancer, for which several clinical trials have already been reported. NKT cells are specifically activated by a synthetic glycolipid, alpha-galactosylceramide (alpha-GalCer). However, it is known that, in human cancer patients, NKT cells express a degree of hyporesponsiveness to alpha-GalCer. In this study, we have examined the mechanism by which hyporesponsiveness to alpha-GalCer can be induced. In cancer-bearing mice, alpha-GalCer-induced NKT cell expansion, cytokine production, cytotoxicity, and antimetastatic effect in vivo were all significantly impaired. In fact, alpha-GalCer could eliminate metastatic disease in naive animals but failed to protect cancer-bearing mice. CD11b(+) Gr-1(+) cells were particularly increased in cancer-bearing mice and were necessary and sufficient for the suppression of the alpha-GalCer response in a nitric oxide-mediated fashion. Administration of a retinoic acid to cancer-bearing mice reduced the population of CD11b(+) Gr-1(+) cells and effectively restored alpha-GalCer-induced protection. These results show a novel feature of NKT cell function in cancer. Furthermore, our data suggest a new strategy to enhance NKT cell-mediated anticancer immune responses by suppressing CD11b(+) Gr-1(+) cell functions.

Topics: Animals; Carcinoma, Lewis Lung; CD11b Antigen; Cell Line, Tumor; Enzyme-Linked Immunosorbent Assay; Galactosylceramides; Interferon-gamma; Interleukin-4; Killer Cells, Natural; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasms, Experimental; Nitric Oxide; Receptors, Chemokine; Spleen; T-Lymphocytes; Time Factors; Tretinoin

Here we describe a family of GPI-anchored cell surface proteins that function as ligands for the mouse activating NKG2D receptor. These molecules are encoded by the retinoic acid early inducible (RAE-1) and H60 minor histocompatibility antigen genes on mouse chromosome 10 and show weak homology with MHC class I. Expression of the NKG2D ligands is low or absent on normal, adult tissues; however, they are constitutively expressed on some tumors and upregulated by retinoic acid. Ectopic expression of RAE-1 and H60 confers target susceptibility to NK cell attack. These studies identify a family of ligands for the activating NKG2D receptor on NK and T cells, which may play an important role in innate and adaptive immunity.

Topics: Amino Acid Sequence; Animals; Carcinoma, Lewis Lung; Cloning, Molecular; Cytotoxicity, Immunologic; Gene Expression Regulation; Glycosylphosphatidylinositols; Humans; Immunoglobulin Fc Fragments; Immunoglobulin G; Killer Cells, Natural; Ligands; Membrane Proteins; Mice; Mice, Inbred C57BL; Minor Histocompatibility Antigens; Molecular Sequence Data; Multigene Family; NK Cell Lectin-Like Receptor Subfamily K; Receptors, Immunologic; Receptors, Natural Killer Cell; Recombinant Fusion Proteins; Tretinoin; Tumor Cells, Cultured

The anti-invasive and anti-metastatic effects with new retinoid 4-acetamidophenyl retinoate (4-APR) were studied using in vitro and in vivo experiments. 4-APR, at the dose of 43.3 mg.kg-1.day-1 p.o., was shown to reduce the spontaneous lung metastatic foci of Lewis lung carcinoma. 4-APR was also found to inhibit the artificial lung metastasis of B16-F10 cells by 67.9% and 36.6% and suppress the reconstituted basement membrane invasion of B16-F10 cells by 54.2% and 41.9% at the concentrations of 10(-5) mol.L-1 and 10(-6) mol.L-1, respectively.

Topics: Animals; Antineoplastic Agents; Carcinoma, Lewis Lung; Humans; Male; Mice; Mice, Inbred C57BL; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Transplantation; Retinoids; Tretinoin; Tumor Cells, Cultured