Apigenin: Selective CK2 inhibitor increases Ikaros expression and improves T cell homeostasis and function in murine pancreatic cancer.

Pancreatic cancer (PC) evades immune destruction by favoring the development of regulatory T cells (Tregs) that inhibit effector T cells. The transcription factor Ikaros is critical for lymphocyte development, especially T cells. We have previously shown that downregulation of Ikaros occurs as a result of its protein degradation by the ubiquitin-proteasome system in our Panc02 tumor-bearing (TB) mouse model.

HLA-DR peptide occupancy can be regulated with a wide variety of small molecules.

HLA-DR is the most commonly expressed and likely the most medically important human MHC class II, antigen presenting protein. In a normal immune response, HLA-DR binds to antigenic peptide and the HLA-DR/peptide complex binds to a T-cell receptor, thus contributing to T-cell activation and stimulation of an immune response against the antigen. When foreign antigen is not present, HLA-DR binds endogenous peptide which, under normal conditions does not stimulate an immune response.

Class II transactivator expression in melanoma cells facilitates T-cell engulfment.

Background/aim: Melanoma cells express high levels of HLA class II, cell surface antigen-presenting proteins, which is an anomalous phenotype among solid tumors. There has never been a satisfying explanation for how this HLA class II-positive phenotype is related to tumor development. Lugini and colleagues demonstrated that melanoma cells have the capacity to engulf T-cells.

An Oct-1-based, feed-forward mechanism of apoptosis inhibited by co-culture with Raji B-cells: towards a model of the cancer cell/B-cell microenvironment.

A continuing conundrum of cancer biology is the dichotomous function of transcription factors that regulate both proliferation and apoptosis, seemingly opposite results. Previous results have indicated that regulated entry into the S-phase of the cell cycle can be anti-apoptotic. Indeed, tumor suppressor genes can be amplified in tumors and certain, slow growing cancers can represent a relatively poor prognosis, both phenomena likely related to reduced cancer cell apoptosis, in turn due to reduced, unproductive entry into S-phase.

Suppression of natural killer cell cytotoxicity in postpartum women: time course and potential mechanisms.

Little is known about the recovery of the immune system from normal pregnancy and whether the postpartum period is a uniquely adapted immune state. This report extends previous observations from our group of decreased natural killer (NK) cell cytotoxicity in the postpartum period. NK cytotoxicity was measured from 1 week through 9 months postpartum.

Regulation of HLA-DR peptide occupancy by histone deacetylase inhibitors.

Numerous molecular effects have been attributed to histone deacetylase inhibitors (HDACI's), including the induction of major histocompatibility (MHC) genes. Here we report that one FDA approved HDACI, Vorinostat, and a second HDACI currently in clinical trials, Entinostat, reduce the ratio of class II associated invariant peptide (CLIP) to the MHC class II molecule, HLA-DR, indicating an increase in the non-CLIP peptides bound to HLA-DR. The HDACI effects are apparent with immortalized B-cells, HLA-DR constitutive melanoma cells and with melanoma cells expressing HLA-DR due to transformation with an expression vector for the HLA-DR gene co-activator, CIITA.

Regulation of interlocking gene regulatory network subcircuits by a small molecule inhibitor of retinoblastoma protein (RB) phosphorylation: cancer cell expression of HLA-DR.

The induction of the major histocompatibility (MHC), antigen-presenting class II molecules by interferon-gamma, in solid tumor cells, requires the retinoblastoma tumor suppressor protein (Rb). In the absence of Rb, a repressosome blocks the access of positive-acting, promoter binding proteins to the MHC class II promoter. However, a complete molecular linkage between Rb expression and the disassembly of the MHC class II repressosome has been lacking.

Preparation of myeloid derived suppressor cells (MDSC) from naive and pancreatic tumor-bearing mice using flow cytometry and automated magnetic activated cell sorting (AutoMACS).

MDSC are a heterogeneous population of immature macrophages, dendritic cells and granulocytes that accumulate in lymphoid organs in pathological conditions including parasitic infection, inflammation, traumatic stress, graft-versus-host disease, diabetes and cancer. In mice, MDSC express Mac-1 (CD11b) and Gr-1 (Ly6G and Ly6C) surface antigens. It is important to note that MDSC are well studied in various tumor-bearing hosts where they are significantly expanded and suppress anti-tumor immune responses compared to naïve counterparts.

Murine pancreatic adenocarcinoma dampens SHIP-1 expression and alters MDSC homeostasis and function.

Background: Pancreatic cancer is one of the most aggressive cancers, with tumor-induced myeloid-derived suppressor cells (MDSC) contributing to its pathogenesis and ineffective therapies. In response to cytokine/chemokine receptor activation, src homology 2 domain-containing inositol 5'-phosphatase-1 (SHIP-1) influences phosphatidylinositol-3-kinase (PI3K) signaling events, which regulate immunohomeostasis. We hypothesize that factors from murine pancreatic cancer cells cause the down-regulation of SHIP-1 expression, which may potentially contribute to MDSC expansion, and the suppression of CD8(+) T cell immune responses.

Trafficking CD11b-positive blood cells deliver therapeutic genes to the brain of amyloid-depositing transgenic mice.

A major question for gene therapy in brain concerns methods to administer therapeutic genes in a uniform manner over major portions of the brain. A second question in neuroimmunology concerns the extent to which monocytes migrate to the CNS in degenerative disorders. Here we show that CD11b+ cells (largely monocytes) isolated from the bone marrow of GFP (green fluorescent protein)-expressing donors spontaneously home to compacted amyloid plaques in the brain.