Acquisition and Presentation of Tumor Antigens by Dendritic Cells.

Dendritic cells (DCs) are master regulators of the immune response and, because of their peculiar features in antigen acquisition, processing, and presentation, they play a critical role in activating an efficient antigenspecific T-lymphocyte response against tumors. However, the DC family is composed of different cell subsets, which may differently contribute to tumor-specific T-cell activation. In addition to the DC subset involved, the induction of a tumor-specific adaptive immune response is also dependent on DC interactions with other innate cell effectors, such as natural killer cells.

NCR(+)ILC3 concentrate in human lung cancer and associate with intratumoral lymphoid structures.

Tertiary lymphoid structures (TLSs) are a common finding in non-small cell lung cancer (NSCLC) and are predictors of favourable clinical outcome. Here we show that NCR(+) innate lymphoid cell (ILC)-3 are present in the lymphoid infiltrate of human NSCLC and are mainly localized at the edge of tumour-associated TLSs. This intra-tumoral lymphocyte subset is endowed with lymphoid tissue-inducing properties and, on activation, produces IL-22, TNF-α, IL-8 and IL-2, and activates endothelial cells.

A non-canonical adenosinergic pathway led by CD38 in human melanoma cells induces suppression of T cell proliferation.

Nucleotide-metabolizing ectoenzymes are endowed with an extracellular catalytic domain, which is involved in regulating the extracellular nucleotide/nucleoside balance. The tumor microenvironment contains high levels of adenosine (ADO) generated by this enzymatic network, thus promoting tumor growth by inhibiting anti-tumor immune responses. ADO inhibition in melanoma murine models limits tumor metastases and restores anti-tumor immune responses.

cells in immunity: Plasmacytoid DCs dress up as cancer cells.

, in immunology, is a term originally coined to indicate the transfer of peptide-MHC complexes belonging to neighboring cells on antigen presenting cells. We have recently shown that plasmacytoid dendritic cells (pDCs) are particularly suited to be cross-dressed by tumor cells and that this phenomenon provides a unique pathway for abundant presentation of tumor antigens by pDCs.

Cross-Talks between Natural Killer Cells and Distinct Subsets of Dendritic Cells.

In recent years, the essential role of bi-directional cross-talk between natural killer (NK) and dendritic cells (DC) during immune responses has been clearly elucidated. In particular, this cross-talk results in the development of an efficient innate response, through DC-mediated NK cell activation, and a potent adaptive immune response, through NK-mediate DC editing and maturation. Recently, some novel human DC subsets have been identified: migratory DCs in afferent lymph and draining lymph nodes; CLEC9A(+)/BDCA3(+) (CD141) DCs in interstitial dermis, liver, lung; inflammatory DCs in several inflammatory fluids.

CD56(bright)perforin(low) noncytotoxic human NK cells are abundant in both healthy and neoplastic solid tissues and recirculate to secondary lymphoid organs via afferent lymph.

As limited information is available regarding the distribution and trafficking of NK cells among solid organs, we have analyzed a wide array of tissues derived from different human compartments. NK cells were widely distributed in most solid tissues, although their amount varied significantly depending on the tissue/organ analyzed. Interestingly, the distribution appeared to be subset specific, as some tissues were preferentially populated by CD56(bright)perforin(low) NK cells, with others by the CD56(dim)perforin(high) cytotoxic counterpart.

Membrane transfer from tumor cells overcomes deficient phagocytic ability of plasmacytoid dendritic cells for the acquisition and presentation of tumor antigens.

The potential contribution of plasmacytoid dendritic cells (pDCs) in the presentation of tumor cell Ags remains unclear, and some controversies exist with regard to the ability of pDCs to phagocytose cell-derived particulate Ags and cross-present them to MHC class I-restricted T lymphocytes. In this study, we show that human pDCs, although inefficient in the internalization of cell membrane fragments by phagocytosis, can efficiently acquire membrane patches and associated molecules from cancer cells of different histotypes. The transfer of membrane patches to pDCs occurred in a very short time and required cell-to-cell contact.

Characterization of human afferent lymph dendritic cells from seroma fluids.

Dendritic cells (DCs) migrate from peripheral tissues to secondary lymphoid organs (SLOs) through the afferent lymph. Owing to limitations in investigating human lymph, DCs flowing in afferent lymph have not been properly characterized in humans until now. In this study, DCs present in seroma, an accrual of human afferent lymph occurring after lymph node surgical dissection, were isolated and analyzed in detail.

Novel perspectives on dendritic cell-based immunotherapy of cancer.

Advances in immunobiology knowledge as well as in cell culture processes that generate large numbers of purified and functionally mature dendritic cells (DCs) have raised the possibility that DCs might represent promising clinical agents to generate effective immune responses against cancer. Here, we discuss the present pitfalls of dendritic cell vaccines for the treatment of human cancer with regard to the most recent knowledge in the biology of DCs. In particular, we highlight the relevance of improving our current understanding of DC trafficking, functions and interactions with other cells of innate immunity for the development of more effective cancer vaccines.

Dendritic cell editing by activated natural killer cells results in a more protective cancer-specific immune response.

Over the last decade, several studies have extensively reported that activated natural killer (NK) cells can kill autologous immature dendritic cells (DCs) in vitro, whereas they spare fully activated DCs. This led to the proposal that activated NK cells might select a more immunogenic subset of DCs during a protective immune response. However, there is no demonstration that autologous DC killing by NK cells is an event occurring in vivo and, consequently, the functional relevance of this killing remains elusive.

A mixture of bacterial mechanical lysates is more efficient than single strain lysate and of bacterial-derived soluble products for the induction of an activating phenotype in human dendritic cells.

Dendritic cells (DCs), following an optimal maturation, are able to drive an efficient immune-response. For this, both co-stimulatory molecules (CD80 and CD86), activation molecules (CD83) and peptide presenting molecules (HLA) are over-expressed. The in vitro treatment of immature DC with fragments of bacterial strains, obtained by using a mechanical lysis as well as with bacterial-derived molecules (such as lipopolysaccharide and protido-glycan), induced the maturation of DCs and the secretion of a panel of cytokines and chemokines.

CD62L expression identifies a unique subset of polyfunctional CD56dim NK cells.

Human natural killer (NK) cells comprise 2 main subsets, CD56(bright) and CD56(dim) cells, that differ in function, phenotype, and tissue localization. To further dissect the heterogeneity of CD56(dim) cells, we have performed transcriptome analysis and functional ex vivo characterization of human NK-cell subsets according to the expression of markers related to differentiation, migration or competence. Here, we show for the first time that the ability to respond to cytokines or to activating receptors is mutually exclusive in almost all NK cells with the exception of CD56(dim) CD62L(+) cells.

Seroma fluid subsequent to axillary lymph node dissection for breast cancer derives from an accumulation of afferent lymph.

Seroma is a frequent complication of breast cancer surgery, the etiology of which remains indefinite. It represents a subcutaneous accumulation of fluid frequently reported after surgical procedures such as axillary lymph node dissection. Despite previous studies have associated seroma fluid to an inflammatory exudate, the surgical removal of draining lymph nodes may indicate that seroma might not represent a mere exudate but rather an accrual of lymph drained from tributary tissues.

NK cells provide helper signal for CD8+ T cells by inducing the expression of membrane-bound IL-15 on DCs.

NK cell recognition of cells that do not express or express low amounts of MHC class I molecules results not only in direct killing of target cells but also in the generation of specific T cell responses consequent to the induction of dendritic cell (DC) activation. While IL-12 production by NK cell-activated DCs is generally thought to play a critical role, a similar DC-mediated NK cell help has been reported also in IL-12-knockout mice. Here, we show that human NK cells can induce on DC surface membrane, via IFN-gamma secretion, the expression of high levels of IL-15.

Arginase 2 is expressed by human lung cancer, but it neither induces immune suppression, nor affects disease progression.

In human prostate cancer, Arginase 2 (ARG2) and nitric oxide synthase (NOS) are concomitantly expressed by tumor cells, and induce tumor immune escape via peroxynitrite-dependent Tyrosine nitrosylation. Since there were no data regarding this immune suppressive mechanism in other tumor types, and an evaluation of its clinical relevance in human tumors had still to be provided, we have investigated presence and clinical relevance of ARG2 and NOS expression in lung cancer. No evidence of NOS expression was found, no significant NOS enzymatic activity was detected.

Natural killer cells infiltrating human nonsmall-cell lung cancer are enriched in CD56 bright CD16(-) cells and display an impaired capability to kill tumor cells.

Background: Despite natural killer (NK) cells being originally identified and named because of their ability to kill tumor cells in vitro, only limited information is available on NK cells infiltrating malignant tumors, especially in humans.

Methods: NK cells infiltrating human nonsmall cell lung cancers (NSCLC) were analyzed with the aim of identifying their potential protective role in an antitumor immune response. Both relevant molecule expression and functions of NK cells infiltrating NSCLC were analyzed in comparison with autologous NK cells isolated from either peritumoral normal lung tissues or peripheral blood.

Role of natural killer cells in the pathogenesis and progression of multiple sclerosis.

Natural killer (NK) cells are a subset of lymphocytes which have long been alleged to play an immunoregulatory role in the prevention of autoimmune diseases. Here, we briefly review NK cell features and the major findings from studies on NK cells in human and animals susceptible to multiple sclerosis (MS). Although most studies in human seem to suggest an association between disease and deficiencies in NK cells, it is also clear that NK cells can be both protective and pathogenic in MS models.

Distinct gut-derived lactic acid bacteria elicit divergent dendritic cell-mediated NK cell responses.

Lactic acid bacteria (LAB) are abundant in the gastrointestinal tract where they continuously regulate the immune system. NK cells are potently activated by dendritic cells (DCs) matured by inflammatory stimuli, and NK cells are present in the gut epithelium and in mesenteric lymph nodes, but it is not known how NK-DC interactions are affected by the predominantly non-pathogenic LAB. We demonstrate that human DCs exposed to different strains of gut-derived LAB consistently induce proliferation, cytotoxicity and activation markers in autologous NK cells.

CD56brightCD16- killer Ig-like receptor- NK cells display longer telomeres and acquire features of CD56dim NK cells upon activation.

Human NK cells can be divided into CD56(dim)CD16(+) killer Ig-like receptors (KIR)(+/-) and CD56(bright)CD16(-) KIR(-) subsets that have been characterized extensively regarding their different functions, phenotype, and tissue localization. Nonetheless, the developmental relationship between these two NK cell subsets remains controversial. We report that, upon cytokine activation, peripheral blood (PB)-CD56(bright) NK cells mainly gain the signature of CD56(dim) NK cells.

NK cells of human secondary lymphoid tissues enhance T cell polarization via IFN-gamma secretion.

Human secondary lymphoid tissues harbor NK cells that predominantly secrete cytokines in response to activation. Here, we demonstrate that these immunoregulatory NK cells assist in the Th1 polarization of primary immune responses, induced by dendritic cells. Tonsilar, but not peripheral blood NK cells enhanced the expansion of IFN-gamma-producing CD4+ T cells via their superior ability to produce IFN-gamma.

Distinctive lack of CD48 expression in subsets of human dendritic cells tunes NK cell activation.

CD48 is a glycosyl phosphatidylinositol anchor protein known to be virtually expressed by all human leukocytes. Its ligand, 2B4, is a signaling lymphocyte activation molecule-related receptor involved in NK cell activation. Because dendritic cells (DCs) are strong inducers of NK cell functions, we analyzed the expression of CD48 in different human DC subsets.

Eosinophil granulocytes account for indoleamine 2,3-dioxygenase-mediated immune escape in human non-small cell lung cancer.

Indoleamine 2,3-dioxygenase (IDO), a catabolizing enzyme of tryptophan, is supposed to play a role in tumor immune escape. Its expression in solid tumors has not yet been well elucidated: IDO can be expressed by the tumor cells themselves, or by ill-defined infiltrating cells, possibly depending on tumor type. We have investigated IDO expression in 25 cases of non-small cell lung cancer (NSCLC).

The abundant NK cells in human secondary lymphoid tissues require activation to express killer cell Ig-like receptors and become cytolytic.

Natural killer cells are important cytolytic cells in innate immunity. We have characterized human NK cells of spleen, lymph nodes, and tonsils. More than 95% of peripheral blood and 85% of spleen NK cells are CD56(dim)CD16(+) and express perforin, the natural cytotoxicity receptors (NCRs) NKp30 and NKp46, as well as in part killer cell Ig-like receptors (KIRs).

IFN-alpha mediates the up-regulation of HLA class I on melanoma cells without switching proteasome to immunoproteasome.

Treatment of melanoma cell lines with IFN-gamma induces the switch from proteasome (PS) to immunoproteasome (iPS). This finding has profound implications for the immunobiology of melanoma cells since certain peptides (such as Melan-A(mart1)(27-35)) are cleaved differently by iPS, thus implying a different ability to be presented by HLA class I molecules. IFN-alpha is a cytokine not only produced during infectious diseases, but also used in the treatment of certain cancers.

The interaction between NK cells and dendritic cells in bacterial infections results in rapid induction of NK cell activation and in the lysis of uninfected dendritic cells.

NK and DC reciprocal interactions have only recently been investigated. In this study, we focused on the interplay between NK cells and DC in two models of bacterial infection. Immature monocyte-derived DC were cultured in the presence of live Escherichia coli or bacillus Calmette-Guérin.