Search

Introduction It is important to decipher the molecular interactions between melanoma cells and various components of the immune system if we are to manipulate the latter for safe and effective [...], NK cells use a variety of receptors to detect abnormal cells, including tumors and their metastases. However, in the case of melanoma, it remains to be determined what specific molecular interactions are involved and whether NK cells control metastatic progression and/or the route of dissemination. Here we show that human melanoma cell lines derived from LN metastases express ligands for natural cytotoxicity receptors (NCRs) and DNAX accessory molecule-1 (DNAM-1), two emerging NK cell receptors key for cancer cell recognition, but not NK group 2 member D (NKG2D). Compared with cell lines derived from metastases taken from other anatomical sites, LN metastases were more susceptible to NK cell lysis and preferentially targeted by adoptively transferred NK cells in a xenogeneic model of cell therapy. In mice, DNAM-1 and NCR ligands were also found on spontaneous melanomas and melanoma cell lines. Interference with DNAM-1 and NCRs by antibody blockade or genetic disruption reduced killing of melanoma cells. Taken together, these results show that DNAM-1 and NCRs are critical for NK cell--mediated innate immunity to melanoma cells and provide a background to design NK cell--based immunotherapeutic strategies against melanoma and possibly other tumors.

Author(s): Thorbald van Hall (corresponding author) [1, 8]; Elisabeth Z Wolpert [2, 8]; Peter van Veelen [1, 3, 8]; Sandra Laban [1]; Michael van der Veer [1]; Marjet Roseboom [1]; [...]

Recently, MHC class I molecules have been shown to be important for the retraction of synaptic connections that normally occurs during development [Huh, G.S., Boulanger, L. M., Du, H., Riquelme, P. A., Brotz, T. M. & Shatz, C. J. (2000) Science 290, 2155-2158]. In the adult CNS, a classical response of neurons to axon lesion is the detachment of synapses from the cell body and dendrites. We have investigated whether MHC I molecules are involved also in this type of synaptic detachment by studying the synaptic input to sciatic motoneurons at I week after peripheral nerve transection in [beta]-microglobulin or transporter associated with antigen processing 1-null mutant mice, in which cell surface MHC I expression is impaired. Surprisingly, lesioned motoneurons in mutant mice showed more extensive synaptic detachments than those in wild-type animals. This surplus removal of synapses was entirely directed toward inhibitory synapses assembled in clusters. In parallel, a significantly smaller population of motoneurons reinnervated the distal stump of the transected sciatic nerve in mutants. MHC I molecules, which traditionally have been linked with immunological mechanisms, are thus crucial for a selective maintenance of synapses during the synaptic removal process in neurons after lesion, and the lack of MHC I expression may impede the ability of neurons to regenerate axons. [beta]2-microglobulin | motoneuron | spinal cord | synapse elimination | nerve lesion

The assumption that the beta-2-microglobulin (beta-2m) of the class I major histocompatibility complex (MHC) molecules is essential for recognition by cytotoxic T lymphocytes (CTLs) was tested. To obtain CTLs, mice were primed with live allogeneic beta-2m-deficient spleen cells or mutant lymphoma cells expressing MHC class I without beta-2m. The results showed that both beta-2m-deficient and beta-2m-expressing lymphoma cells were rejected in allogeneic mice, but only beta-2m-deficient cells induced CTLs. The results show that beta-2m is not essential for MHC class I presentation to CTLs.

Cytotoxic T-cells may be activated by the presentation of a specific antigen. This presentation takes place when a competent cell degrades a foreign protein into peptide fragments, which are then bound by molecules of the major histocompatibility complex (MHC). In humans, molecules of the MHC are often called HLA antigens, or human leukocyte antigen. Molecules of the MHC are then brought to the cell surface along with their peptide fragment. The 'cytotoxic' set of T-cells are only capable of recognizing an antigen when it is properly presented by a class I histocompatibility molecule. However, an unresolved question has been whether class I molecules can be expressed on the surface of cells without the presence of a peptide antigen fragment. Researchers have shown that when mouse lymphoma cells are cultured at reduced temperatures, between 19 and 33 degrees Centigrade, class I molecules not binding antigen fragments were detected on the cell surface. However, when the temperature of these cells is raised to 37 degrees, close to body temperature, the class I molecules quickly disappeared. These results suggest that the antigen fragment has a stabilizing effect on the class I molecular complex. Without this action, the complex is unstable at body temperature, and is undetected. At lower temperatures, the complex is more stable. The use of temperature to control the expression of class I molecules will likely aid in the study of these molecules and to a better understanding of their role in the immune response. (Consumer Summary produced by Reliance Medical Information, Inc.)

Patients with leukemia or certain genetic diseases can be treated by transplantation of bone marrow or hematopoietic stem cells. The patient's own bone marrow (and leukemia cells residing in the [...]

Author(s): Klas Kärre (corresponding author); Gunter Schneider [1] Class I molecules of the major histocompatibility complex (MHC) are normally expressed on the surface of most cells in the body. They [...]

Viruses avoid destruction by T cells through masking their presence by not expressing major histocompatibility complex (MHC) molecules. However, natural killer (NK) cells destroy any cells that do not express MHC molecules. Some viruses, including cytomegalovirus, have been found to evade detection and destruction by natural killer (NK) cells as well by adopting a decoy approach and expressing a homologue of normal MHC molecules.

Conventional wisdom has it that the lymphocytes defend the body from infectious agents and aberrant cells by recognizing the 'foreign,' detecting nonself proteins in the body fluids or on surfaces [...]

Prevention of Allogeneic Bone Marrow Graft Rejection by H-2 Transgene in Donor Mice ACCEPTANCE AND REJECTION OF skin grafts can be predicted from the transplantation laws, reflecting the control of [...]

Focuses on the in vivo basis for murine cytomegalovirus (MCMV) resistance to killing by natural killer (NK) cells. Resistance against infections by NK cells; Dual function of MCMV.

Discusses a study that investigates the effect of major histocompatibility complex (MHC) receptors on natural killer (NK) cells. Function of MHC class I molecules in the immune system; expression of MHC; Description of an immunoglobulin-type receptor, KIR2DL2, which is the focus of the study; Difference between MHC receptors in mice and humans.

Immune checkpoint blockade therapy has changed prognoses for many melanoma patients. However, immune responses that correlate with clinical progression of the disease are still poorly understood. To identify immune responses correlating with melanoma clinical evolution, we analyzed serum cytokines as well as circulating NK and T-cell subpopulations from melanoma patients. The patients' immune profiles suggested that melanoma progression leads to changes in peripheral blood NK and T-cell subsets. Stage IV melanoma was characterized by an increased frequency of CCR7 + CD56 bright NK cells as well as high serum concentrations of the CCR7 ligand CCL19. CCR7 expression and CCL19 secretion were also observed in melanoma cell lines. The CCR7 + melanoma cell subpopulation coexpressed PD-L1 and Galectin-9 and had stemness properties. Analysis of melanoma-derived cancer stem cells (CSC) showed high CCR7 expression; these CSCs were efficiently recognized and killed by NK cells. An accumulation of CCR7 + , PD-L1 + , and Galectin-9 + melanoma cells in melanoma metastases was demonstrated ex vivo Altogether, our data identify biomarkers that may mark a CCR7-driven metastatic melanoma pathway., (©2019 American Association for Cancer Research.)