Making cold malignant pleural effusions hot: driving novel immunotherapies

Murthy, Pranav; Ekeke, Chigozirim N.; Russell, Kira L.; Butler, Samuel C.; Wang, Yue; Luketich, James D.; Soloff, Adam C.; Dhupar, Rajeev; Lotze, Michael T.

doi:10.1080/2162402x.2018.1554969

Cited by 57 publications

(75 citation statements)

References 248 publications

(252 reference statements)

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“…PE is a symptom caused by more than 50 diseases and is usually classified as malignant pleural effusion (MPE) or benign pleural effusion (BPE). The incidence of MPE is higher than 200,000 cases/year in the United States [2] , with lung cancer (36%) and breast cancer (26%) accounting for the vast majority of cases due to metastasis to the pleura [ 3 , 4 ]. With regard to BPE, tuberculous pleurisy effusion (TPE) is the most common cause [5] and a prominent problem in developing countries, including China [6] .…”

Section: Introductionmentioning

confidence: 99%

Development and validation of a novel scoring system developed from a nomogram to identify malignant pleural effusion

Wang

Tian

et al. 2020

EBioMedicine

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Background This study aimed to establish and validate a novel scoring system based on a nomogram for the differential diagnosis of malignant pleural effusion (MPE) and benign pleural effusion (BPE). Methods Patients with PE and confirmed aetiology who underwent diagnostic thoracentesis were included in this study. One retrospective set ( N = 1261) was used to develop and internally validate the predictive model. The clinical, radiological and laboratory features were collected and subjected to logistic regression analyses. The primary predictive model was displayed as a nomogram and then modified into a novel scoring system, which was externally validated in an independent set ( N = 172). Findings The novel scoring system was composed of fever (3 points), erythrocyte sedimentation rate (4 points), effusion adenosine deaminase (7 points), serum carcinoembryonic antigen (CEA) (4 points), effusion CEA (10 points) and effusion/serum CEA (8 points). With a cutoff value of 15 points, the area under the curve, specificity and sensitivity for identifying MPE were 0.913, 89.10%, and 82.63%, respectively, in the training set, 0.922, 93.48%, 81.51%, respectively, in the internal validation set and 0.912, 87.61%, 81.36%, respectively, in the external validation set. Moreover, this scoring system was exclusively applied to distinguish lung cancer with PE from tuberculous pleurisy and showed a favourable diagnostic performance in the training and validation sets. Interpretation This novel scoring system was developed from a retrospective study and externally validated in an independent set based on six easily accessible clinical variables, and it exhibited good diagnostic performance for identifying MPE. Funding grants (no. 81572942, no. 81800094).

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Section: Introductionmentioning

confidence: 99%

Development and validation of a novel scoring system developed from a nomogram to identify malignant pleural effusion

Wang

Tian

et al. 2020

EBioMedicine

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“…In malignant pleural mesothelioma, a primary tumor of the pleura, tumor samples have an immune signature of elevated T regs and MDSCs that contribute to the anergy of tumor-infiltrating lymphocytes (TILs) and correlate with survival [ 14 ]. Notably, the functional capacity of the immune cells in mesothelioma has been demonstrated [ 15 , 16 , 17 ]. Nevertheless, at about 2500 cases per year in the United States, mesothelioma represents a very small burden of pleural disease when compared with over 150,000 annual MPEs in patients with advanced epithelial cancers.…”

Section: Introductionmentioning

confidence: 99%

“…The number of T cells in proximity to pleural tumor is generally quite large in MPEs, and the study of their potential functionality or conversely, of the cellular and soluble factors in the effusion that contribute to T cell quiescence, has been evolving [ 15 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. Even with T cell directed immunotherapy, there are many hurdles the MPE environment might present for successful antitumor activity.…”

Section: Introductionmentioning

confidence: 99%

Characteristics of Malignant Pleural Effusion Resident CD8+ T Cells from a Heterogeneous Collection of Tumors

Dhupar

Okusanya

Eisenberg

et al. 2020

IJMS

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While T cell-based cancer immunotherapies have shown great promise, there remains a need to understand how individual metastatic tumor environments impart local T cell dysfunction. At advanced stages, cancers that metastasize to the pleural space can result in a malignant pleural effusion (MPE) that harbors abundant tumor and immune cells, often exceeding 108 leukocytes per liter. Unlike other metastatic sites, MPEs are readily and repeatedly accessible via indwelling catheters, providing an opportunity to study the interface between tumor dynamics and immunity. In the current study, we examined CD8+ T cells within MPEs collected from patients with heterogeneous primary tumors and at various stages in treatment to determine (1) if these cells possess anti-tumor activity following removal from the MPE, (2) factors in the MPE that may contribute to their dysfunction, and (3) the phenotypic changes in T cell populations that occur following ex vivo expansion. Co-cultures of CD8+ T cells with autologous CD45― tumor containing cells demonstrated cytotoxicity (p = 0.030) and IFNγ production (p = 0.003) that inversely correlated with percent of myeloid derived suppressor cells, lactate, and lactate dehydrogenase (LDH) within the MPE. Ex vivo expansion of CD8+ T cells resulted in progressive differentiation marked by distinct populations expressing decreased CD45RA, CCR7, CD127, and increased inhibitory receptors. These findings suggest that MPEs may be a source of tumor-reactive T cells and that the cellular and acellular components suppress optimal function.

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“…Therefore, varying levels of IL-6 pleural fluid in malignant pleural effusions can arise in varying tumor progression, stage, and metastases in the pleural space. 19 NLR is the ratio of absolute neutrophils to lymphocytes, and generally neutrophil levels correlate with the degree of inflammation and disease progression, whereas lymphocytes correlate with the body's defence system against disease. Research by Akturk et al in 2016 stated that pleural fluid NLR was lower in tuberculous pleural effusions than malignant pleural effusions.…”

Section: Discussionmentioning

confidence: 99%

Role of pleural fluid interleukin-6, neutrophil-lymphocyte ratio, and monocyte-lymphocyte ratio in distinguishing tuberculous and malignant pleural effusions

et al. 2021

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Background: Pleural effusion is caused by various disease, including tuberculosis infection and malignancy. To determine the etiology, immunologic parameters are needed to distinguish tuberculous and malignant pleural effusions, including pleural fluid interleukin-6 (IL-6), neutrophil-lymphocyte ratio (NLR), and monocyte-lymphocyte ratio (MLR).Methods: This was a cross-sectional study, conducted at Sanglah General Hospital in Denpasar from March 2020 to September 2020. Pleural fluid IL-6 and leucocyte differential count were measured from subjects with tuberculous and malignant pleural effusions.Results: There were 22 tuberculous pleural effusion subjects with mean pleural fluid IL-6 9269.017±902.211 pg/ml, median (range) pleural fluid NLR 0.123 (0.044-9.449), and MLR 0.065 (0.044-0.355). There were 31 subjects with malignant pleural effusions, with mean pleural fluid IL-6 8212.146±2022.350 pg/ml, median pleural fluid NLR 0.189 (0.015-2.599), and MLR 0.065 (0.010-0.254). Pleural fluid IL-6 in tuberculous pleural effusions were significantly higher (p=0.014). With a pleural fluid IL-6 cut-off ≥9147.959 pg/ml, sensitivity of 63.6% and specificity of 64.5% were obtained. Pleural fluid NLR and MLR of the two groups were not significantly different (p=0.807 and p=0.116).Conclusions: Pleural fluid IL-6 in tuberculous pleural effusions is higher than malignant pleural effusions, with a cut-off of ≥9147.959 pg/ml, tuberculous pleural effusions can be diagnosed with sensitivity of 63.6% and specificity of 64.5%. There is no difference in pleural fluid NLR and MLR in tuberculous and malignant pleural effusions.

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Making cold malignant pleural effusions hot: driving novel immunotherapies

Cited by 57 publications

References 248 publications

Development and validation of a novel scoring system developed from a nomogram to identify malignant pleural effusion

Development and validation of a novel scoring system developed from a nomogram to identify malignant pleural effusion

Characteristics of Malignant Pleural Effusion Resident CD8+ T Cells from a Heterogeneous Collection of Tumors

Role of pleural fluid interleukin-6, neutrophil-lymphocyte ratio, and monocyte-lymphocyte ratio in distinguishing tuberculous and malignant pleural effusions

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