Blocking CCL2 nitration in tumors promoted CD8+ influx and reduced tumor growth and prolonged survival in mice when combined with adoptive cell therapy.

SummaryT cell antigen receptor (TCR) and coreceptor ligation is thought to initiate signal transduction by inducing activation of the kinase Lck. Here we showed that catalytically active Lck was present in unstimulated naive T cells and thymocytes and was readily detectable in these cells in lymphoid organs. In naive T cells up to ∼40% of total Lck was constitutively activated, part of which was also phosphorylated on the C-terminal inhibitory site. Formation of activated Lck was independent of TCR and coreceptors but required Lck catalytic activity and its maintenance relied on monitoring by the HSP90-CDC37 chaperone complex to avoid degradation. The amount of activated Lck did not change after TCR and coreceptor engagement; however it determined the extent of TCR-ζ phosphorylation. Our findings suggest a dynamic regulation of Lck activity that can be promptly utilized to initiate T cell activation and have implications for signaling by other immune receptors.

No abstract

Poly(ADP-ribosylation) is a post-translational modification of proteins playing a crucial role in many processes, including DNA repair and cell death. The best known poly(ADP-ribosylating) enzyme, PARP-1, is a DNA nick sensor and uses betaNAD(+) to form polymers of ADP-ribose which are further bound to nuclear protein acceptors. To strictly regulate poly(ADP-ribose) turnover, its degradation is assured by the enzyme poly(ADP-ribose) glycohydrolase (PARG). During apoptosis, PARP-1 plays two opposite roles: its stimulation leads to poly(ADP-ribose) synthesis, whereas caspases cause PARP-1 cleavage and inactivation. PARP-1 proteolysis produces an 89 kDa C-terminal fragment, with a reduced catalytic activity, and a 24 kDa N-terminal peptide, which retains the DNA binding domains. The fate and the possible role of these fragments during apoptosis will be discussed.

Human natural killer (NK) cells express IntroductionInnate immunity plays a crucial role in limiting or even in eradicating pathogens during the early phases of primary infections, before T and B cells can mount efficient adaptive responses. Natural killer (NK) cells, phagocytes, and other innate effector cells do not require clonal expansion to mediate their function and can enter and defend a tissue almost as soon as it becomes infected. These effector cells can eliminate pathogens by different mechanisms, including killing of infected cells and secretion of cytokines and chemokines, which promote inflammation and may further recruit/activate other cells of the innate immunity. In many instances, the prompt and different reactions of the innate immunity to pathogen invasion can lead to termination of infection with no further involvement of the adaptive immunity and no development of manifest disease. In addition, thanks to their interaction with dendritic cells, NK cells may influence the magnitude and the quality of subsequent adaptive immune responses. [1][2][3][4][5][6] Recent advances in understanding the biologic role of different cell types of the innate immunity include mainly the discovery and the molecular characterization of an array of cell surface receptors. The structure and the evolution of genes coding for these receptors reflect mostly the need to adapt to mechanisms of pathogen evasion. A key example is represented by the human leukocyte antigen (HLA) class I-specific human killer immunoglobulin (Ig)-like receptor (KIR)-encoding genes. KIRs belong to the Ig superfamily and, in most instances, recognize determinants shared by groups of HLA-A, HLA-B, or HLA-C allotypes. [7][8][9][10][11] From an evolutionary point of view, all KIRs derive from an ancestral molecule composed of 3 Ig-like domains, D0, D1, and D2 (KIR3D), and a long cytoplasmic tail. The predominant human KIRs are characterized by 2 Ig-like domains (KIR2Ds). 12 There are 2 types of KIR2Ds: the first type (including KIR2DL1/L2/L3 and KIR2DS1/S2/S3/S4/S5) is composed of domains homologous to D1 and D2. The majority of these KIRs are specific for HLA-C molecules. KIRs belonging to the second type contain domains homologous to D0 and D2 (KIR2DL4/L5). KIRs composed of 3 Ig domains are specific either for the HLA-Bw4 group of alleles (KIR3DL1 and possibly KIR3DS1) 13 or for some HLA-A alleles (KIR3DL2). 14,15 All KIRs, with the exception of KIR2DL4, display a clonally distributed expression in human NK cells. 7,16,17 KIRs were also detected on a small subset of cytolytic T lymphocytes 18,19 and in the Sézary cutaneous T-cell lymphoma, in which both infiltrating and circulating malignant T cells are characterized by KIR3DL2 expression. 20,21 Cells of the innate immune system of vertebrates recognize pathogen-associated molecular patterns and undergo activation mainly through specialized molecules called Toll-like receptors (TLRs). NK cells express different TLRs including TLR2, 22 TLR5, 23 TLR7, 24 TLR3, and TLR9. 25 Upon interaction wit...

It has long been known that in vitro polarized macrophages differ in morphology. Stemming from a conventional immunohistology observation, we set out to test the hypothesis that morphology of tumor-associated macrophages (TAMs) in colorectal liver metastasis (CLM) represents a correlate of functional diversity with prognostic significance. Density and morphological metrics of TAMs were measured and correlated with clinicopathological variables. While density of TAMs did not correlate with survival of CLM patients, the cell area identified small (S-TAM) and large (L-TAM) macrophages that were associated with 5-yr disease-free survival rates of 27.8% and 0.2%, respectively (P < 0.0001). RNA sequencing of morphologically distinct macrophages identified LXR/RXR as the most enriched pathway in large macrophages, with up-regulation of genes involved in cholesterol metabolism, scavenger receptors, MERTK, and complement. In single-cell analysis of mononuclear phagocytes from CLM tissues, S-TAM and L-TAM signatures were differentially enriched in individual clusters. These results suggest that morphometric characterization can serve as a simple readout of TAM diversity with strong prognostic significance.

these findings provide evidence in support of a role of NKp30 and its major ligand in HCC development and evolution. This article is protected by copyright. All rights reserved.

Mesenchymal stem cells (MSC) represent a promising therapeutic approach in many diseases in view of their potent immunomodulatory properties, which are only partially understood. Here, we show that the endothelium is a specific and key target of MSC during immunity and inflammation. In mice, MSC inhibit activation and proliferation of endothelial cells in remote inflamed lymph nodes (LNs), affect elongation and arborization of high endothelial venules (HEVs) and inhibit T-cell homing. The proteomic analysis of the MSC secretome identified the tissue inhibitor of metalloproteinase-1 (TIMP-1) as a potential effector molecule responsible for the anti-angiogenic properties of MSC. Both in vitro and in vivo, TIMP-1 activity is responsible for the anti-angiogenic effects of MSC, and increasing TIMP-1 concentrations delivered by an Adeno Associated Virus (AAV) vector recapitulates the effects of MSC transplantation on draining LNs. Thus, this study discovers a new and highly efficient general mechanism through which MSC tune down immunity and inflammation, identifies TIMP-1 as a novel biomarker of MSC-based therapy and opens the gate to new therapeutic approaches of inflammatory diseases.