Situación clínica de infección por SARS-Cov-2 en pacientes con carcinoma broncogénico: Contexto Actual / Sars-Cov-2 Infection in patients with lung cancer: current clinical context

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Molecular subtyping reveals immune alterations associated with progression of bronchial premalignant lesions.

Bronchial premalignant lesions (PMLs) are precursors of lung squamous cell carcinoma, but have variable outcome, and we lack tools to identify and treat PMLs at risk for progression to cancer. Here we report the identification of four molecular subtypes of PMLs with distinct differences in epithelial and immune processes based on RNA-Seq profiling of endobronchial biopsies from high-risk smokers. The Proliferative subtype is enriched with bronchial dysplasia and exhibits up-regulation of metabolic and cell cycle pathways. A Proliferative subtype-associated gene signature identifies subjects with Proliferative PMLs from normal-appearing uninvolved large airway brushings with high specificity. In progressive/persistent Proliferative lesions expression of interferon signaling and antigen processing/presentation pathways decrease and immunofluorescence indicates a depletion of innate and adaptive immune cells compared with regressive lesions. Molecular biomarkers measured in PMLs or the uninvolved airway can enhance histopathological grading and suggest immunoprevention strategies for intercepting the progression of PMLs to lung cancer.

[Immunotherapy of Bronchogenic Carcinoma and Its Perspectives]. / Imunoterapie u bronchogenního karcinomu a její perspektivy.

Immunotherapy is becoming another possible alternative in the treatment of lung cancer. It is a completely different method of treating cancer which is not directed to the tumor itself, but to the immune system. Surface antigens present on tumor cells may be an effective and specific therapeutic targets and strategies based on antibodies inhibiting immune check-points significantly improves the antitumor immune response. Monoclonal antibody blocking CTLA 4 (cytotoxic T-lymphocyte antigen) and PD 1 receptor (protein programmed cell death) and its ligand PD L1 showed clinical efficacy and nivolumab (antiPD 1) was approved in 2nd line treatment squamous nonsmall cell lung cancer.

Expansion of myeloid-derived suppressor cells in chronic obstructive pulmonary disease and lung cancer: potential link between inflammation and cancer.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a risk factor for lung cancer (LC). Myeloid-derived suppressor cells (MDSCs) down-regulate the T cell receptor ζ chain (TCR ζ) through L-arginine deprivation and lead to T cell dysfunction and deficient antitumor immunity. We hypothesized that abnormally high levels of MDSCs in COPD patients may alter tumor immunosurveillance. METHODS: We compared the proportion of circulating MDSCs (Lin-HLA-DR-/CD33+/CD11b+) (by flow cytometry), arginase I (ARG I) serum levels (by ELISA), and expression levels of TCR ζ on circulating lymphocytes (by flow cytometry) in 28 patients with LC, 62 subjects with COPD, 41 patients with both LC and COPD, 40 smokers with normal spirometry and 33 non-smoking controls. T cell proliferation assays were performed in a subgroup of participants (CFSE dilution protocol). RESULTS: We found that: (1) circulating MDSCs were up-regulated in COPD and LC patients (with and without COPD); (2) MDSCs expansion was associated with TCR ζ down-regulation in the three groups; (3) in LC patients, these findings were independent of COPD and tobacco smoking exposure; (4) TCR ζ down-regulation correlates with T cell hyporesponsiveness in COPD and LC patients. CONCLUSIONS: These results suggest that tumor immunosurveillance might be impaired in COPD and may contribute to the increased risk of LC reported in these patients.

Blockade of TNF-alpha decreases both inflammation and efficacy of intrapulmonary Ad.IFNbeta immunotherapy in an orthotopic model of bronchogenic lung cancer.

Adenoviral immuno-gene therapy using interferon-beta has been effective in an orthotopic model of lung cancer. However, pulmonary inflammation induced by adenoviral (Ad) vectors will almost certainly limit the maximally tolerated dose. On the other hand, the strong innate immune response generated by the vector may be helpful in initiating the adaptive immune response required for efficacy. The goals of this study were to develop an effective approach to inhibit Ad.IFNbeta-mediated acute pulmonary inflammation and to determine whether this reduction of Ad-mediated inflammation decreased the therapeutic efficacy of Ad.IFNbeta in a mouse model of bronchioloalveolar cancer. Our data show that anti-TNF-alpha antibodies can blunt the innate pulmonary immune response induced by Ad vectors, even in sensitized animals. However, this effect also inhibited the ability of the animal to generate anti-tumor immune responses and reduced survival in an orthotopic lung cancer model responsive to Ad.IFNbeta treatment. Interestingly, in a flank model of tumor using a cell line derived from the lung tumor, TNF-alpha blockade did not inhibit efficacy. These data suggest that the innate immune response to adenovirus in the lung may be important in immuno-gene therapy of lung cancer. Therapeutic application of anti-inflammatory therapy in immuno-gene therapy strategies should thus be undertaken with caution.

Intrapulmonary IFN-beta gene therapy using an adenoviral vector is highly effective in a murine orthotopic model of bronchogenic adenocarcinoma of the lung.

Given previous work showing that an adenoviral vector expressing IFN-beta (Ad.IFNbeta) was highly effective in eradicating i.p. mesothelioma tumors, the antitumor efficacy of this agent was evaluated in an orthotopic model of bronchogenic adenocarcinoma of the lung. These transgenic mice have a conditionally expressed, oncogenic K-rasG12D allele that can be activated by intratracheal administration of an adenovirus expressing Cre recombinase (Ad.Cre). K-rasG12D mutant mice were given Ad.Cre intranasally to activate the oncogene. Mice were then given 10(9) plaque-forming units of a control vector (Ad.LacZ) or Ad.IFNbeta intranasally 3 and 4 weeks later, a time when lung tumors had been established. Cells derived from K-ras-mutated lung tumors were also grown in the flanks of mice to study mechanisms of therapeutic responses. In two separate experiments, untreated tumor-bearing mice all died by day 57 (median survival, 49 days). Ad.LacZ-treated mice all died by day 71 (median survival, 65 days). In contrast, 90% to 100% of mice treated with Ad.IFNbeta were long-term survivors (>120 days; P < 0.001). In addition, immunity to re-challenge with tumor cells was induced. In vitro and flank tumor studies showed that Ad.IFNbeta induced direct tumor cell killing and that depleting natural killer or CD8+ T cells, but not CD4+ T cells, with antibodies attenuated the effect of Ad.IFNbeta. These studies, showing remarkable antitumor activity in this orthotopic lung cancer model, provide strong preclinical support for a trial of Ad.IFNbeta to treat human non-small cell lung cancer.

El tabaco como alérgeno en enfermedad bronquial obstructiva. Estudio preliminar / Tobacco as an allergen in bronchial obstructive disease: preliminary report

En España, 56.000 personas mueren al año por enfermedades asociadas al hábito de fumar. Pero se ha estudiado poco la influencia de este hábito en el asma extrínseca. En estudios publicados, la prueba cutánea y las concentraciones de IgE específica en el suero verificaron una sensibilización al tabaco, pero no se han realizado estudios alergológicos completos en series amplias de pacientes. Objetivos: Investigar si una respuesta específica alérgica al tabaco puede asociarse a la aparición del asma alérgica, el asma intrínseca, la EPOC y el carcinoma broncógeno. Métodos: Seleccionamos de forma aleatoria 3 grupos de pacientes: 60 con asma polínica, 60 pacientes no atópicos con obstrucción bronquial (20 con asma intrínseca, 20 con EPOC, 20 con carcinoma broncogénico) y 60 controles. Se realizó un estudio en vivo: prick con extracto de tabaco; provocación bronquial (PB) con cigarrillo encendido, apagado y extracto de hoja fresca de tabaco; prueba epicutánea con extracto de tabaco y nicotina. Y también un estudio de laboratorio: IgE específica a tabaco por CAP y EAST, immunoblotting e inhibición de EAST). Resultados: La proporción de fumadores activos fue del 42% (índice tabáquico del 28,7%). Un 17,83% de los pacientes presentaron, frente al extracto de tabaco, respuestas positivas en prick y en la PB con una IgE específica > 0,35 kU/l, sin ninguna relación con la edad pero sí con el sexo masculino (p 0,35 kU/l) y la provocación bronquial (p < 0,001). La sensibilización al tabaco fue mayor en el grupo de asmáticos polínicos (30%) que en los grupos con EPOC y carcinoma, y negativa en asma intrínseca y en los controles. La positividad del prick y del parche no dependió del número de cigarrillos ni del número de años de hábito tabáquico, pero la respuesta bronquial se asoció significativamente al número de años de hábito (p < 0,001) y al número de cigarrillos fumados en el caso de los exfumadores (p < 0,007). La respuesta dual en la PB fue más frecuente en los pacientes con EPOC (p < 0,001). La positividad (en el prick y la IgE) al tabaco se asoció a la sensibilización al látex (p < 0,002) y a los pólenes de Artemisia vulgaris (p < 0,006) y Lolium perenne (p < 0,001), pero no a otras solanáceas ni al resto de los alérgenos probados. Se demostró reactividad cruzada entre el polen de Lolium perenne y el tabaco por inhibición de EAST y del immunoblotting. Conclusiones: Demostramos que el tabaco se puede comportar como un alérgeno capaz de provocar una respuesta inflamatoria a través de un mecanismo inmunitario mediado por IgE específica. Así como en el asma ocupacional se ha observado que el hábito de fumar se asocia a una expresión temprana de la enfermedad, es posible que también aumente la expresión clínica de otros tipos de asma extrínseca y de la EPOC. El perfil de esta sensibilización corresponde a agricultores varones de mediana edad con una media de hábito de 20 años. La sensibilización es más frecuente en los polínicos por la posible reactividad cruzada entre los alérgenos vegetales. Se observó una mayor posibilidad de sensibilidad del tipo IV en los pacientes con EPOC, lo que sugiere que una respuesta inmunitaria frente al tabaco podría haber influido en el desarrollo de su inflamación crónica bronquial (AU)

Background: Asthma and chronic obstructive pulmonary disease (COPD) are two devastating clinical problems and major causes of morbidity and mortality in worldwide. Although asthma may originate soon after birth, the natural history of the disease and the influence of tobacco habits are poorly understood. Skin test and specific IgE level have verified the existence of tobacco sensitisation. However, the very few published studies report conflicting results concerning the clinical significance of tobacco IgE. Objective: The aim of our study was to investigate if a specific allergenic response against tobacco might influence the development of different obstructive bronchial diseases: allergenic and intrinsic asthma, bronchial carcinoma and COPD. Methods: We performed an observational study on the effects of tobacco exposure in 3 groups of subjects: 60 patients suffered from grass-pollen asthma, 60 patients with non-allergy bronchial obstructive disease (20 patients diagnosed as having COPD, 20 having intrinsic asthma, 20 suffered from bronchial carcinoma) and 60 healthy controls that were randomly chosen. All these patients were tested in order to try to identify tobacco as a possible allergen that might cause clinical specific response (pricktests, specific IgE to tobacco and related allergens, bronchial challenge, patch tests with tobacco and nicotin) and immunological response: immunoblotting and EAST-inhibition. Results: The proportion of current smokers was 42% (tobacco index 28.7%). Positive prick and positive BC with specific IgE > 0.35 kU/l was demonstrated in 17.8% of the patients, significantly in men and farmers; 57% of these patients were atopic. The association among positive prick, IgE and BC were good (p < 0.001). Tobacco sensitisation was negative in intrinsic asthma and controls. Positive BC was related with the number of years of habit (p < 0.0001) and tobacco index in patients who had stopped smoking (p < 0.007). Delayed bronchial response and positive patch response were more common in patients with COPD (p < 0.002) than in patients suffering from other pathologies. Tobacco IgE level was related with sensitisation to latex (p < 0.002) and pollens from mugwort p < 0.006) and Lolium perenne (p < 0.001), but not with other vegetables that belong to the Solanaceae family. EAST-inhibition showed the existence of cross-reactivity between tobacco and Lolium perenne pollen. Conclusions: Tobacco may be responsible of a specific IgE response. Smoking time, tobacco index and male sex were all related with positive specific response to tobacco. This smoking-induced allergenic response may be associated to different obstructive bronchial diseases as COPD and bronchial carcinoma. Patients with asthma due to pollen, farmers and patients also sensitised to latex were the people with more positive responses to tobacco, possibly due to a cross-reactivity between vegetal and tobacco allergens (AU)

Aquaporin expression in human lymphocytes and dendritic cells.

Aquaporins (AQPs) are molecular water channels, and 10 related AQPs have been identified in mammals. So far, the study of mammalian AQP expression has been limited mainly to mice and rat lung, kidney, brain, and gastrointestinal tract. Although AQP3 and AQP7 have been shown to be involved in volume-regulating mechanisms in dendritic cells, the exact patterns of AQP expression in the human immune system are not well understood. Using reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of peripheral blood from healthy donors, we demonstrated the expression of AQP1, AQP3, and AQP5 in activated B and T lymphocytes and the expression of AQP3 and AQP5 in immature dendritic cells. None of the tested AQPs was expressed in inactivated B or T lymphocytes. In situ hybridization studies using human tonsils showed that AQP1, AQP3, and AQP5 were expressed almost exclusively in the germinal centers. Further in situ hybridization showed that expression of AQP1, AQP3, and AQP5 were detected in tumor-infiltrating lymphocytes surrounding bronchogenic carcinoma of the lung and that expression of AQP3 and AQP5 was detected in dendritic cells. These findings provide new insights into the expression patterns of AQPs in the human immune system. While the exact role of AQPs in the human immune system remains to be determined, we propose that AQP expression patterns may be used as a marker to study lymphocyte activation and proliferation.

Indices of immune activation after bronchial carcinoma surgery.

The aim of the study was to examine the levels of IL-2 and soluble receptor sIL-2R involved in the activation of TH1 lymphocytes, C-reactive protein (CRP) and serum amyloid A (SAA), whose synthesis is induced by IL-6 and IL-1, in the patients with bronchial carcinoma subjected to surgical procedures. The studies involved 35 patients operated on for bronchial carcinoma and 17 patients requiring thoracic surgery due to other reasons. The immune parameters were determined preoperatively and three, seven, 10 days after the operation. The control group consisted of 22 healthy individuals whose parameters were determined only once. The analysis revealed that the serum IL-2 level found in the patients was three times higher than that in controls. Moreover, the average sIL-2 level was also statistically higher in the group of patients. The results obtained three days after the procedure showed decreased IL-2 levels in both groups subjected to surgery (due to bronchial carcinoma or other reasons). The findings of subsequent determinations performed seven and 10 days after the operation showed that the values observed 10 days after surgery were higher than the preoperative ones. The sIL-2 levels three days after the operation significantly increased in both groups of patients, however, on next examinations they started to vary; the slL-2R decreased in the bronchial carcinoma patients and increased in the other group. The results of CRP and SAA examinations revealed higher values in the bronchial carcinoma patients compared to controls. The SAA levels were extremely high (82.54 in patients and 3.17microg/ml in controls). The postoperative levels of this protein showed a similar tendency--a rapid postoperative increase and gradual normalization in subsequent examinations. However, in both cases the values observed 10 days after the operation were higher than those in the control group. An extremely high increase in SAA levels after surgery (82.54-preoperatively versus 961.6 microg/ml-postoperatively) is noteworthy. Our preliminary results on the immune indices after bronchial carcinoma surgery are consistent with those observed after the operations for other neoplastic tumours; decreased levels of serum IL-2 in the postoperative period need further studies concerning the postoperative administration of exogenous IL-2.

Transfection of E-cadherin cDNA in human lung tumor cells reduces invasive potential of tumors.

Lung cancer is a major health-care problem in industrialized countries. With reference to its therapeutic consequences and major histological variations, it is divided into two subgroups - SCLC (small-cell lung cancer) and NSCLC (non-small-cell lung cancer). As an important factor of cell-cell and cell-substratum interaction, cell adhesion molecules (CAMs) seem to play a key role in tumor-cell migration and invasion that lead to metastases. We investigated human lung tumor cell lines established from histologically documented neoplastic lesions taken in our operating theater. Immunohistological screening showed differences in E-cadherin expression with no clear predominance of SCLC or NSCLC cell lines. Using an invasion model with Matrigel Matrix and a migration assay, we could demonstrate a more aggressive behavior pattern in E-cadherin-negative cell lines. We transfected E-cadherin cDNA into a formerly negative cell line showing strong invasive behavior in the initial tests in order to investigate the role of E-cadherin in this process. In this study, we examined E-cadherin cDNA transfection in human bronchial carcinoma cells. At present, transfection is stable with a follow-up time of one year. We could demonstrate that cell lines were remarkably less invasive after transfection of E-cadherin in the invasion model with Matrigel Matrix. These results indicate that the E-cadherin CAM plays an important role in lung tumor invasion and metastasis. Further studies are in progress to confirm these findings and to describe a possible role of this CAM in tumor therapy.

Diseases caused by asbestos: mechanisms of injury and disease development.

Asbestos is a ubiquitous, naturally occurring fiber that has been linked to the development of malignant and fibrotic diseases of the lung and pleura. These diseases may be initiated by injury to epithelial cells and mesothelial cells by asbestos fibers through the formation of reactive oxygen intermediates. Elaboration of oxidants are also a consequence of inflammation, a hallmark of exposure to asbestos after inhalation or injection of asbestos fibers into animals. The type, size, and durability of asbestos fibers may be important in toxicity and pathogenicity of asbestos types. This review discusses the pathways of oxidant generation by asbestos fibers, cell-cell interaction that may initiate and perpetuate inflammation, cytokine release and proliferative responses to asbestos, and cell signaling pathways implicated in these events.

[Immunomorphology of lymph nodes and prognosis in lung cancer]. / Immunomorfologia linfonodale e prognosi nel cancro del polmone.

BACKGROUND: Many studies have investigated locoregional immune responses and long-term survival in various types of cancer; few have focused on lung cancer. This study was designed to assess the prognostic value of immunomorphologic changes in locoregional lymph nodes in patients resected for bronchogenic carcinoma. METHODS: In a retrospective analysis, immune responses in locoregional lymph nodes were studied histologically in 172 selected patients. Lymph node morphology was studied according to the system of Cottier et al.: sinus histiocytosis (SH) and paracortical lymphoid cell hyperplasia (PCA) were considered as a cellular immune response, and follicular hyperplasia of the cortical area (CA) as a humoral reaction. The survival rate was estimated by the Kaplan-Meier product-limit method. Log-rank test and Cox proportional-hazards model were used to determine statistical significance in univariate and multivariate survival analysis. RESULTS: 35.5% of the patients had no evident response in regional nodes; 19.8% had a marked cellular response; 11% a marked humoral response; and 33.7% a mixed cellular-humoral response. A nodal cellular response improved long-term survival rates even in patients with regional node metastases. Multivariate analysis identified an independent variable as having high prognostic value: lymph node immunoreactivity. CONCLUSIONS: Lymph node immunoreactivity significantly influences long-term survival after curative surgery for lung cancer and may be useful in stratifying patients for prospective trials of adjuvant treatment including immunotherapy.

BAL neopterin : a novel marker for cell-mediated immunity in patients with pulmonary tuberculosis and lung cancer.

BACKGROUND: Neopterin is derived from guanosine triphosphate and is produced by stimulated macrophages under the influence of gamma-interferon of lymphocyte origin. It has been suggested that it is an excellent marker for the activation of the monocyte/macrophage axis in some clinical situations. However, to our knowledge, the relationship of BAL neopterin levels to disease states has not been studied. AIM: To assess the usefulness of BAL neopterin levels as an index of disease activity in patients with pulmonary tuberculosis and lung cancer. METHODS: BAL and serum neopterin levels were evaluated in 20 patients with pulmonary tuberculosis, 20 patients with bronchogenic carcinoma, and 10 healthy individuals. The concentration of neopterin was evaluated by radioimmunoassay technique. The BAL level of neopterin was standardized using the BAL urea level. RESULTS: The neopterin levels (mean +/- SD) in the BAL and serum of tuberculous patients (88.6 +/- 27.4 nmol/L epithelial lining fluid [ELF], 61.3 +/- 29.4 nmol/L, respectively) were significantly higher when compared with those in lung cancer patients (40.7 +/- 16.6 nmol/L ELF, 26.8 +/- 6.58 nmol/L, respectively, p < 0.001) and when compared with those in control subjects (26.3 +/- 11.3 nmol/L ELF, 6.8 +/- 2.7 nmol/L, respectively, p < 0.001). In the tuberculous group, BAL and serum neopterin levels in patients with far-advanced disease were significantly higher when compared with those in patients with moderately and minimally advanced diseases (p < 0.001). BAL and serum neopterin levels were significantly higher in patients with small cell carcinoma than in those with adenocarcinoma (p < 0.05). BAL neopterin levels were significantly (p < 0.001) higher than serum levels in all patients and control groups. In addition, there were significant positive correlations between BAL and serum neopterin levels in tuberculous (r = 0.92, p < 0.001), lung cancer (r = 0.62, p < 0.001), and control groups (r = 0.93, p < 0.001). CONCLUSIONS: The levels of neopterin in BAL fluid may reflect the degree of disease activity in pulmonary tuberculous patients. In addition, BAL neopterin levels are elevated in patients with lung cancer, especially the small-cell carcinoma type.

Host defense and survival in patients with lung carcinoma.

BACKGROUND: Numerous studies have investigated locoregional immune responses and long term survival in patients with various types of cancer; few have focused on patients with lung carcinoma. The current study was designed to assess the prognostic value of immunomorphologic changes in locoregional lymph nodes and lymphocytic infiltration of primary tumor (LI) in patients who undergo resection for bronchogenic carcinoma. METHODS: In a retrospective analysis, immune responses in locoregional lymph nodes and at primary tumor sites were studied histologically in 172 selected patients. Lymph node morphology was studied according to the system of Cottier et al. Sinus histiocytosis and paracortical lymphoid cell hyperplasia were considered to be cellular immune responses, and follicular hyperplasia of the cortical area was considered to be a humoral reaction. LI was classified with Black's method. The survival rate was estimated by using the Kaplan-Meier product-limit method. The log rank test and the Cox proportional-hazards model were used to determine statistical significance in univariate and multivariate survival analyses. RESULTS: Among the 172 patients, 35.5% had no evident response in regional lymph nodes, 19.8% had a marked cellular response, 11% had a marked humoral response, and 33.7% had a mixed cellular and humoral response. LI was intense in 36.6% of patients and was absent or scarcely evident in 63.4%. A lymph node cellular response and marked LI improved long term survival rates even in patients with regional lymph node metastases. Multivariate analysis identified two independent variables that had high prognostic value: lymph node immunoreactivity and LI. CONCLUSIONS: Lymph node immunoreactivity and LI significantly influence long term survival after curative surgery for patients with carcinoma of the lung and may be useful in stratifying patients for prospective trials of adjuvant treatment, including immunotherapy.

Pulmonary malignancies in the immunocompromised patient.

Clinicians should be familiar with immunodeficiency-related malignancies, as their incidence is expected to increase further with the rise in the number and survival of immunocompromised patients. The most common malignancies affecting the lungs in those patients are Kaposi's sarcoma, non-Hodgkin's lymphoma and, to a far less extent, Hodgkin's disease and bronchogenic carcinoma. However, their relative frequency depends on the types of immune deficiency, including those due to congenital disorders, AIDS and drug treatments. This review will summarize epidemiological data on the frequency of immmunodeficiency-related malignancies, recent advances on their pathogenesis and current approaches to their diagnosis and treatment in the various immunosuppressed groups.

T-cell receptor biases and clonal proliferations in blood and pleural effusions of patients with lung cancer.

We sought evidence that pulmonary carcinomas mediate a cellular immunologic response by analyzing T-cell antigen receptor beta-chain variable gene (TCRBV) repertoires of lymphocytes from peripheral blood (PBL) and malignant pleural effusions (PEL) of five lung cancer patients. Expression levels of 27 TCRBV were quantitated by multiprobe RNase protection assay (RPA), and clonal expansions were identified by sequence enrichment nuclease assay (SENA) and junctional region sequencing. Abnormal TCRBV expansions were identified in all subjects by RPA (mean 6.9 +/- 1.7/patient), and their number closely correlated with elapsed time since initial diagnosis (r = 0.97). SENA, performed in specimens from three patients, confirmed the presence of mono or oligoclonality in 48% of abnormal RPA expansions, and further identified T-cell clones among TCRBV with normal expression levels. The majority of clonal expansions were among PEL, and were nearly equally divided between CD4 and CD8. These data show that T-cell repertoires of lung cancer patients are characterized by marked abnormalities and frequent clonal expansions, most likely representing responses to unique, tumor-specific antigens (TSA). Moreover, this process appears exaggerated among PEL, further suggesting that malignant effusions include local proliferations of tumor reactive T cells. These findings imply the presence of lung cancer TSA capable of eliciting cellular immune responses and raise the possibility that selective immunotherapies can ultimately be developed.

Dendritic cells with a potent accessory activity are present in human exudative malignant pleural effusions.

Dendritic cells are human leucocyte antigen (HLA)-DR positive accessory cells, that play a critical role in the development of cell-mediated immune reactions. Since the pleural space is frequently involved in cell-mediated immune reactions, we sought to isolate dendritic cells from pleural fluid. Pleural effusion mononuclear cells (PEMCs) were obtained by Ficoll centrifugation of exudative pleural effusions recovered from 19 patients with malignant pleurisy. After double-step adherence, firmly-adherent mononuclear cells (FAMs) and loosely-adherent mononuclear cells (LAMs) were recovered. The latter cells were centrifuged on a bovine plasma albumin gradient to obtain a loosely-adherent low density fraction. Nonadherent cells were rosetted with sheep red blood cells (SRBC) to obtain a nonadherent nonrosetting (NANR) cell fraction. Mitomycin C-treated PEMCs, NANRs, FAMs, and LAMs served as stimulatory cells in mixed leucocyte reaction experiments. 3H-thymidine incorporation by purified normal allogeneic blood T-lymphocytes was assessed as an index of accessory cell function. The phenotype of NANR, FAM and LAM cells was characterized using single and double stainings with a panel of monoclonal antibodies (MoAbs). Accessory cell (AC) activity (counts per minute (cpm) x 10(3)(+/-SE); 2.5 x 10(4) AC x well(-1) of LAM (148+/-24) and NANR (108.4+/-11.2) was greater than that observed for FAM (59.3+/-9.4) and for unfractioned PEMC (13.8+/-4.9). The FAM fraction was virtually entirely composed of CD68+ HLA-DR+ mononuclear phagocytes. NANR and LAM contained 51+/-12% and 65+/-6% HLA-DR+ cells, respectively, and most HLA-DR positive cells were negative for CD3, CD19, and CD68, markers for T-, B-lymphocytes and mononuclear phagocytes. Moreover, both NANR and LAM fractions contained significant numbers of cells bearing the RFD1 surface marker, expressed on dendritic cells. These results suggest that dendritic cells are present in exudative pleural effusions, and that they may be involved in the development of cell-mediated immune reactions in the pleural space.

[Liberation of neopterin after lung resecting interventions with and without bronchial carcinoma]. / Freisetzung von Neopterin nach lungenresezierenden Eingriffen mit und ohne Bronchialcarcinom.

Neopterin has been suggested as a marker for the activation of macrophages, as indicated in several malignant tumors. We therefore studied 63 patients undergoing thoracic surgery, including lung tissue resection. These patients were prospectively monitored regarding the release of neopterin and other mediators of cellular immune reaction (PMN-elastase, CRP, sIL-2-R, PGE2). Our study revealed that surgical interventions in lung adenocarcinomas resulted in a marked (P < or = 0.01) and long-lasting (5 days) release of neopterin and sIL-2-R postoperatively. In contrast, the so-called inflammatory mediators (CRP, PMN-elastase) were only transiently increased. When comparing these findings in lung carcinoma with operations on benign tumors of the lung, on the basis of our results we conclude that the carcinoma per se obviously induces a distinct immune reaction. This, however, may be caused by surgical manipulation of the tumor during tissue resection. No prognostic value has been found so far for the release of neopterin regarding survival and/or recurrence of tumor.