Search

Harnessing the immune system to fight cancer is an exciting advancement in lung cancer therapy. Antitumor immunity can be augmented by checkpoint blockade therapy, which removes the inhibition/brakes imposed on the immune system by the tumor. Checkpoint blockade therapy with anti-programmed cell death protein 1 (anti-PD-1)/anti-programmed death ligand 1 (anti-PDL-1) antibodies causes tumor regression in about 25% of patients with lung cancer. In another approach, the immune system is forced or accelerated to attack the tumor through augmentation of the antitumor response against mutations carried by each lung tumor. This latter approach has become feasible since the advent of next-generation sequencing technology, which allows identification of the specific mutations that each individual lung tumor bears. Indeed lung cancers are now known to have high mutation rates, making them logical targets for mutation-directed immune therapies. We review how sequencing of lung cancer mutations leads to better understanding of how the immune system recognizes tumors, providing improved opportunities to track antitumor immunity and ultimately leading to the development of personalized vaccine strategies aimed at unleashing the host immune system to attack mutations in the tumor. [ABSTRACT FROM AUTHOR]

Chemotherapy and immunotherapy can be either synergistic or antagonistic modalities in the treatment of cancer. Cytotoxic chemotherapy not only affects the tumor but also targets dividing lymphocytes, the very cells that are required to develop an immune response. For this reason, chemo- and immunotherapy have been seen as antagonistic. However, cell death can be immunogenic and the way in which chemotherapeutic drug kills a tumor cell is likely to be an important determinant of how that dying cell interacts with the immune system and whether the interaction will lead to an immune response. When a cell dies as the result of infection, the immune system responds rapidly and the system of Toll-like receptors (TLR) plays a key role in this process. In this review, we will briefly summarize the intracellular signaling pathways that link TLR ligation with immune activation and we will address the questions where and how TLRs recognize their targets.Cell Death and Differentiation (2008) 15, 13–20; doi:10.1038/sj.cdd.4402255; published online 16 November 2007 [ABSTRACT FROM AUTHOR]

The inflammatory and immune cell populations of the human lung parenehyma have not been characterized in detail. This report describes a novel and efficient procedure for their extraction. Histologically normal human lung tissue samples from pneumonectomy specimens were sliced to 0.5 mm. and digested in collagenasc/DNAse. Viable mononuclear cell yields ranged from 15-48 × 106/g, and were markedly in excess of reported methods employing mechanical tissue disruption. which normally yield populations containing almost exclusively macrophages. The lung digest population was examined by flow cytometry using monoclonal antibodies against cell surface receptors. and found to comprise up to 40%, T lymphocytes, 10%, B lymphocytes and 30%, macrophages. contaminated by < 1%, peripheral blood cells. Based upon these figures. the recoverable lung parenchymal lymphoid cell pool appears considerably larger than previously recognized, being of the same order as the peripheral blood pool. Initial functional studies suggest that such cellular activities as antigen-specific T cell proliferation, antigen- presentation interleukin 1 production and natural killer cell activity survive the extraction process and controlled enzymatic digestion experiments with peripheral blood cells indicate that the degree of enzyme-mediated damage to these functions and to cell- surface Structures, was minimal. The extraction method thus appears suitable for studying the types and functions of human parenchymal lung cells in health and disease. [ABSTRACT FROM AUTHOR]

Detachment of epithelial structures from underlying basement membrane (BM) represents an important component of a number of human disease processes e.g. airway and alveolar diseases, gastrointestinal ulceration, and retinal diseases. This study describes a method of evaluating human epithelial cell detachment from BM that is simple, rapid, inexpensive, quantifiable and which, because it utilizes BM rather than tissue culture plastic, more closely mimics the in vivo situation than other methods. In this model human amnionic epithelial cells attached to their underlying BM are isolated from fresh placentae and mounted in a multi-well chemotaxis assembly. These membranes can be studied with the epithelial cell monolayer intact. Protease-induced detachment of the epithelial cells from the underlying BM was readily quantifiable using light microscopy and spectroscopy. Following removal of the native amnionic epithelial cells, immunoperoxidase staining for the BM attachment proteins laminin, fibronectin, and type IV collagen demonstrated that these molecules remain intact.The BM could also be used as an attachment surface to reconstitute other epithelial cell monolayers.Cultured human amnionic cells and human respiratory epithelial cells were both able to attach to the denuded BM in the absence of serum (% attachment = 85 ± 15% and 92 ± 8% respectively, P = 0· 8).Natural BM was a better substrate for epithelial cell attachment than tissue culture plastic in that, in the absence of serum, cultured epithelial ceil attachment to tissue culture plastic was 20 7plusmn; 4% of the value for BM (P < 0· 05). Furthermore, cells attached to plastic adhered less effectively than to BM in that trypsin concentrations required to induce 50% cell detachment were 0·72 ± 0·4 for plastic and 62± 13 BAEE U/mL for BM (P<07middot;001).In view of the complex protein interactions known to be involved in the anchorage of human epithelial cells to BM, it is likely this model will be a useful tool for evaluating the mechanisms underlying human epithelial cell attachment and detachment in a variety of normal and disease situations. [ABSTRACT FROM AUTHOR]

Asbestos exposure is associated with an increased incidence of several mulignances, including malignant mesothelioma (MM), This study evaluates the relationship between asbestos exposure and the in vitro generation and function or LAK cells, an immune effector cell population with powerful lytic activity against MM cells. Both serpentine (chrysotile) and amphibole (amosite and crocidolite) forms of asbestos fibres suppress LAK cell generation, viability (by 5-11%, P < 0.02) and cell recovery (by 13-15%, P < 0.02). However, the LAK cells generated in the presence of the amphiboles were as effective as unexposed cells in lysing both standard tumour cell targets (K562, 56.4% lysis versus 61.5%, respectively, P < 0.5, NS; Daudi, 60.5% lysis vervus 64.5% P > 0.5; NS), and MM tumour cell targets (mean of three MM cell lines 48.3% versus 46.3%, P > 0.5; NS), whereas the function of LAK cells generated in the presence of chrysotile was significantly reduced against three out of the five tumour cell targets tested (P < 0.03). In the presence of asbestos fibres, LAK cell function was reduced against all five tumour cell targets (P < 0.01), irrespective of whether the cell donors were healthy individuals or patients with MM. NK cell activity was also suppressed (P < 0.01). The serpentine form of asbestos, chrysotile, was significantly more suppressive of both effector cell functions than either of the amphiboles (P < 0.001). These findings suggest that asbestos exposure may suppress the function and in some instances the generation of immune effector cell mechanisms, thereby increasing the risk of disease and malignancy. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells are thought to play a role in host defence against malignancy and infection, in immunoregulation and as precursor cells in a generation of lymphokine-activated killer (LAK) cells which can lyse NK-resistant tumour cells. As the lung is a major site for malignancy and infection and as there are large numbers of lymphoid cells including NK- cells in the interstitial compartment of the lung, we evaluated the capacity of interleukin-2 (IL-2), a lymphokine capable of augmenting NK activity in vitro, to augment lung NK cell activity in vivo, using different routes of IL-2 administration. We compared both systemic (i.v. and i.p.) and local (intrapleural and inhalation) routes of IL-2 administration (50000 U/daily for 5 days) using CBA mice, assessing NK and LAK cell activity in the spleen (systemic) and in the lung. The target cells used for these studies were the YAC-1 (NK-sensitive)and P815, NO36 and HA56 (NK-resistant LAK-sensitive) cell lines. Splenic NK activity was increased by 1.4 -1.9-fold for i.v./i.p., respectively, compared with controls with both systemic routes of administration, and lung NK activity was increased 3.2-fold and 3.8-fold (i.v./i.p. respectively, P<0.05), to levels which were comparable to systemic (splenic) NK activity following the same therapy. Intrapleural IL-2 administration similarly enhanced lung NK activity (3.3-fold) and splenic NK activity (1.3-fold; P<0.05 versus controls for both). Surprisingly, inhaled IL-2 suppressed both splenic and lung NK cell activity (84±8% and 78±10%, suppression, respectively, P<0.05). LAK cell activity was also enhanced in the lung by 1.8 8-fold in response to i.v., i.p. and intrapleural IL-2, whereas inhaled IL-2 was ineffective in generating LAK cell activity. These results suggest that the systemic and intrapleural administration of IL-2 effectively boost pulmonary NK and LAK activity whereas inhalation of IL-2 does not. Thus, in clinical situations where boosting of local lung NK or LAK cell activity is desired, these routes of IL-2 administration may be effective. [ABSTRACT FROM AUTHOR]

Alveolar macrophages (AM) are thought to play a key role in the regulation of Immune responses within the lung. While it is well established that AM inhibit T-cell proliferation in vitro, it is unclear whether other aspects of the T-cell activation process are also inhibited. The present study demonstrates that AM from rat, mouse and human differ markedly in the potency with which they inhibit mitogen-induced T-cell proliferation, although in humans the degree of inhibition approaches that observed in the animal systems, if antigen (as opposed to mitogen) is employed as the T-cell activating agent. Rodent and human AM also differ in the mechanisms employed to achieve this inhibition; rodent AM appear to utilize reactive nitrogen intermediates, while this does not appear to be the case for human AM. Despite these differences, T cells stimulated in the presence of AM display a similar phenotype in all species examined, i.e. CD3 down-modulation, up-regulation of interleukin-2 receptor (IL-2R) expression and IL-2 production, but inability to respond to IL-2. Thus, AM appear to allow T-cell activation and expression of T-cell effector function, while selectively inhibiting T-cell proliferation. [ABSTRACT FROM AUTHOR]

The characteristics of the T-cell population in the healthy human lung have been investigated by analysing the properties of T-cell clones derived from bronchoalveolar lavage (BAL) samples and comparing them with T cells cloned from the blood of the same individuals. The proportions of CD4+ and CD8+ T cells in the starting populations from HAL and blood were similar although only 14% of BAL T cells were CD45RA+ compared to 70% of blood T cells. The precursor frequency of T-cell clones derived from BAL was less than from blood. The cytokine profiles [after phytohaemagglutinin (PHA) stimulation] of the clones derived from both sources were markedly different and these differences lay in the CD4+ population. BAL-derived CD4+ clones produced interferon-γ (IFN-γ) more frequently than did those from blood while blood-derived clones were more likely to produce interleukin-2 (IL-2) than those from BAL. IL-4 was produced by the majority of BAL- or blood-derived clones (93% and 88% respectively) either along with IFN-γ (BAL) or lL-2 (blood). The cytokine profiles of BAL-derived T-cell clones are consistent with those derived from lung interstitium and suggest that the BAL T-cell populations reflect those in the lung wall. Whether the unique properties of lung T cells are acquired after leaving the blood or whether there is selective entry of T-cell subpopulations into the lung remains to be determined. [ABSTRACT FROM AUTHOR]

This study evaluates the frequency and functions of immunocompetent T cells at the clonal level in solid human lung tissue versus peripheral blood. Enzymatic digestion of slices of histologically normal human lung yielded 18-42 × 106 viable mononuclear cells per gram wet weight tissue, of which 60-72% were lymphocytes; based upon these recoveries and the known weight of adult lung, the (median) lung parenchymal lymphocyte population can be estimated as 6 × 109, being of the same order as the blood pool and 1 5-30-fold that recoverable by broncho-alveolar lavage. flow cytometric analysis indicated that the bulk of these lymphocytes was OKT3+/T11+ (CD3/CD2) T cells. Purified blood and lung T cells from each subject were cultured at limiting dilution in the presence of PHA, irradiated feeder cells and recombinant human IL-2. The mean frequency estimates for PHA-responsive I cells in these populations were 1 in 1-23 (81%) and 1 in 3-22 (31%) for blood and lung, respectively. This difference was seen for T cells from each donor and was highly significant by paired t-test (P < 0.002). Analysis of surface phenotypes and functions of individual blood and T- cell clones indicated comparable frequencies for OKT4 (CD4) and OKT8 (CD8) expression, TNF production and mitogenainduced cytotoxicity. However, a striking inverse relationship was observed between the overall frequency of IL-2-producing clones (79% for blood venus 47% for lung) and interferon-gamma (IFN-γ)-producing clones (46% versus 87%). These differences were found for each subject, and both were highly significant (P < 0.00l) by paired t-test. The available literature suggests that the majority of these lung T cells represent transient immigrants derived from the blood. Accordingly, the functional differences we have observed suggest either selective trapping within the lung vascular bed of peripheral blood T cells of certain functional phenotypes or alternatively selection/modulation of T cells by lung-derived factors during their transit through the tissue. [ABSTRACT FROM AUTHOR]

The article presents a case study on myocardial metastasis from carcinoma of pancreas presenting as acute myocardial infarction found on a 92-year-old man admitted to hospital having symptoms of transient vertebrobasilar ischaemia. In this report, the authors indicated the position of the metastasis anatomically consistent with the acute electrocardiographic changes. Also, the authors warn clinician for possible etiology with patients having sudden dysrhythmias and signs of pericardial disease.