scholarly journals Small Cell Lung Cancer Neuroendocrine Subtypes are Associated with Different Immune Microenvironment and Checkpoint Molecule Distribution

2020 ◽  
Author(s):  
David Dora ◽  
Christopher Rivard ◽  
Hui Yu ◽  
Paul Bunn ◽  
Kenichi Suda ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Density ◽  
Cell Lung Cancer ◽  
Immune Cell ◽  
Small Cell ◽  
Cell Infiltration ◽  
Immune Checkpoints ◽  
Small Cell Lung ◽  
Primary Tumors

ABSTRACTSmall cell lung cancer (SCLC) has recently been sub-categorized into neuroendocrine (NE)- high and NE-low subtypes showing ‘immune desert’ and ‘immune oasis’ phenotypes, respectively. We aimed to characterize the immune cell localization and the microenvironment according to immune checkpoints and NE subtypes in human SCLC tissue samples at the protein level. In this cross-sectional study, we included 32 primary tumors and matched lymph node (LN) metastases of resected early-stage, histologically confirmed SCLC patients, which were previously clustered into NE subtypes using NE-associated key RNA genes. Immunohistochemistry (IHC) was performed on FFPE TMAs with antibodies against CD45, CD3, CD8 and immune checkpoints including poliovirus receptor (PVR) and Indoleamine 2,3-dioxygenase (IDO).According to our results, the stroma was significantly more infiltrated by immune cells both in primary tumors and LN metastases (vs tumor cell nests). Immune (CD45+) cell density was significantly higher in tumor nests (110.6 ± 24.95 vs 42.74 ± 10.30, cell/mm2, p= 0.0048), with increased CD8+ effector T cell infiltration (21.81 ± 5.458 vs 3.16 ± 1.36 cell/mm2, p < 0.001) in NE-low vs NE-high tumors. Furthermore, the expression of IDO was confirmed on stromal and endothelial cells, and it positively correlated (r= 0.755, p<0.01) with higher immune cell density both in primary tumors and LN metastases, regardless of the NE pattern. Expression of IDO in tumor nests was significantly higher in NE-low (vs NE-high) primary tumors. PVR expression was significantly higher in NE-low (vs NE-high) patients both in primary tumors) and LN metastases.To our knowledge, this is the first human study that demonstrates in situ that NE-low tumors are associated with increased immune cell infiltration compared to NE-high tumors. PVR and IDO are potential new targets in SCLC, with increased expression in the NE-low subtype, providing key insight for further prospective studies on potential biomarkers and targets for SCLC immunotherapies.

scholarly journals Bioinformatics analysis of the circRNA–miRNA–mRNA network for non-small cell lung cancer

2020 ◽  
Vol 48 (6) ◽  
pp. 030006052092916 ◽  
Author(s):  
Xueying Cai ◽  
Lixuan Lin ◽  
Qiuhua Zhang ◽  
Weixin Wu ◽  
An Su
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Cell ◽  
Nsclc Patient ◽  
Small Cell ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Small Cell Lung ◽  
Hub Genes

Objective Non-small cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancers, but its pathogenesis has not been fully elucidated. Therefore, it is valuable to explore the pathogenesis of NSCLC to improve diagnosis and identify novel treatment biomarkers. Methods Circular (circ)RNA, micro (mi)RNA, and gene expression datasets of NSCLC were analyzed to identify those that were differentially expressed between tumor and healthy tissues. Common genes were found and pathway enrichment analyses were performed. Survival analysis was used to identify hub genes, and their level of methylation and association with immune cell infiltration were analyzed. Finally, an NSCLC circRNA–miRNA–mRNA network was constructed. Results Eight miRNAs and 211 common genes were identified. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed that cell projection morphogenesis, blood vessel morphogenesis, muscle cell proliferation, and synapse organization were enriched. Ten hub genes were found, of which the expression of DTL and RRM2 was significantly related to NSCLC patient prognosis. Significant methylation changes and immune cell infiltration correlations with DTL and RRM2 were also detected. Conclusions hsa_circ_0001947/hsa-miR-637/RRM2 and hsa_circ_0072305/hsa-miR-127-5p/DTL networks were constructed, and identified molecules may be involved in the occurrence and development of NSCLC.

scholarly journals Immune Cell Infiltration May Be a Key Determinant of Long-Term Survival in Small Cell Lung Cancer

2019 ◽  
Vol 14 (7) ◽  
pp. 1286-1295 ◽  
Author(s):  
Prasuna Muppa ◽  
Simone Barreto Siqueira Parrilha Terra ◽  
Anurag Sharma ◽  
Aaron S. Mansfield ◽  
Marie-Christine Aubry ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Cell ◽  
Small Cell ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Small Cell Lung ◽  
Term Survival

scholarly journals PD-L1 expression and tumor immune-cell infiltration in non-small cell lung cancer from HIV-infected patients

2016 ◽  
Vol 27 ◽  
pp. vi24
Author(s):  
M. Wislez ◽  
C. Domblides ◽  
M. Antoine ◽  
C. Hamard ◽  
N. Rabbe ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Cell ◽  
Small Cell ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Small Cell Lung

scholarly journals Biomarkers and Gene Signatures to Predict Durable Response to Pembrolizumab in Non-Small Cell Lung Cancer

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3828
Author(s):  
Anello Marcello Poma ◽  
Rossella Bruno ◽  
Iacopo Pietrini ◽  
Greta Alì ◽  
Giulia Pasquini ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Cell ◽  
Small Cell ◽  
Small Cell Lung ◽  
First Line ◽  
Durable Response ◽  
Nsclc Patients

Pembrolizumab has been approved as first-line treatment for advanced Non-small cell lung cancer (NSCLC) patients with tumors expressing PD-L1 and in the absence of other targetable alterations. However, not all patients that meet these criteria have a durable benefit. In this monocentric study, we aimed at refining the selection of patients based on the expression of immune genes. Forty-six consecutive advanced NSCLC patients treated with pembrolizumab in first-line setting were enrolled. The expression levels of 770 genes involved in the regulation of the immune system was analysed by the nanoString system. PD-L1 expression was evaluated by immunohistochemistry. Patients with durable clinical benefit had a greater infiltration of cytotoxic cells, exhausted CD8, B-cells, CD45, T-cells, CD8 T-cells and NK cells. Immune cell scores such as CD8 T-cell and NK cell were good predictors of durable response with an AUC of 0.82. Among the immune cell markers, XCL1/2 showed the better performance in predicting durable benefit to pembrolizumab, with an AUC of 0.85. Additionally, CD8A, CD8B and EOMES showed a high specificity (>0.86) in identifying patients with a good response to treatment. In the same series, PD-L1 expression levels had an AUC of 0.61. The characterization of tumor microenvironment, even with the use of single markers, can improve patients’ selection for pembrolizumab treatment.

scholarly journals P1.04-03 Suppressive Immune Cell Profiling in Patients with Non-Small Cell Lung Cancer

2018 ◽  
Vol 13 (10) ◽  
pp. S526
Author(s):  
J. Koh ◽  
K.Y. Lee ◽  
B. Kim ◽  
M.S. Kim ◽  
H.J. Cho ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Cell ◽  
Small Cell ◽  
Small Cell Lung

scholarly journals Fragmentation of Small-cell Lung Cancer Regulatory States in Heterotypic Microenvironments

2020 ◽  
Author(s):  
Dylan L. Schaff ◽  
Shambhavi Singh ◽  
Kee-Beom Kim ◽  
Matthew D. Sutcliffe ◽  
Kwon-Sik Park ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Single Cell ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Neuroendocrine Cells ◽  
Fluctuation Analysis ◽  
Alveolar Type ◽  
Small Cell Lung ◽  
Primary Tumors

AbstractSmall-cell lung cancers derive from pulmonary neuroendocrine cells, which have stemlike properties to reprogram into other cell types upon lung injury. It is difficult to uncouple the plasticity of these transformed cells from heritable changes that evolve in primary tumors or select in metastases to distant organs. Approaches to single-cell profiling are also problematic if the required sample dissociation activates injury-like signaling and reprogramming. Here, we defined cell-state heterogeneities in situ through laser capture microdissection-based 10-cell transcriptomics coupled with stochastic-profiling fluctuation analysis. Using labeled cells from a small-cell lung cancer mouse model initiated by neuroendocrine deletion of p53 and Rb, we profiled cell-to-cell transcriptional-regulatory heterogeneity in spheroid cultures and liver colonies seeded intravenously. Fluctuating transcripts in vitro were partly shared with other epithelial-spheroid models, and candidate heterogeneities increased considerably when cells were delivered to the liver. Colonization of immunocompromised animals drove the fractional appearance of alveolar type II-like markers and poised cells for paracrine stimulation from immune cells and hepatocytes. Immunocompetency further exaggerated the fragmentation of tumor states in the liver, yielding mixed stromal signatures evident in bulk sequencing from autochthonous tumors and metastases. We identified dozens of transcript heterogeneities that recur irrespective of biological context; their mapped orthologs brought together observations of murine and human small-cell lung cancer. Candidate heterogeneities recurrent in the liver also stratified primary human tumors into discrete groups not readily explained by molecular subtype. We conclude that heterotypic interactions in the liver and lung are an accelerant for intratumor heterogeneity in small-cell lung cancer.Statement of significanceThe single-cell regulatory heterogeneity of small-cell lung cancer becomes increasingly elaborate in the liver, a common metastatic site for the disease.

scholarly journals Immunotherapy for Advanced Small Cell Lung Cancer: A Case Report

2021 ◽  
Vol 6 (5) ◽  
Author(s):  
Wang J ◽  
Deng C ◽  
Zhu X ◽  
Zou X ◽  
Wang J
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Malignant Tumors ◽  
Small Cell ◽  
Immune Checkpoints ◽  
Small Cell Lung ◽  
Advanced Stages ◽  
Made In

In recent years, extraordinary achievements have been made in treating tumor immune checkpoints as targets, which significantly contributes to the research and development of novel immunologic drugs and their application in treating malignant tumors. However, few immunologic drugs can be administered to treat Small Cell Lung Cancer (SCLC). Currently, the focus of most clinical studies is placed on treating SCLC with a combination of immunotherapy and chemotherapy, which is relatively expensive and not covered by medical insurance, thus imposing a heavy economic burden on patients. Meanwhile, obvious adverse reactions occur during chemotherapy, which is still unacceptable to many patients and hence has not yet been widely adopted in clinical practice. Therefore, whether immunotherapy alone can help patients with SCLC, improve their quality of life, and prolong their survival time is a topic we will study in the future. In this case, an attempt was made to apply camrelizumab, an immunologic drug, in the treatment of SCLC in advanced stages, and a favorable efficacy was achieved.

scholarly journals Establishment of a non-small-cell lung cancer-liver metastasis patient-derived tumor xenograft model for the evaluation of patient-tailored chemotherapy

2019 ◽  
Vol 39 (7) ◽  
Author(s):  
Xue Yang ◽  
Gaopei Meng
Keyword(s):  
Lung Cancer ◽  
Liver Metastasis ◽  
Tumor Growth ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Tumor Xenograft ◽  
Small Cell Lung ◽  
Primary Tumors ◽  
Ifn Γ

Abstract In order to optimize patient-tailored chemotherapy, a non-small-cell lung cancer (NSCLC)-liver metastasis patient-derived tumor xenograft (PDTX) model is developed. Computed tomography (CT)-guided NSCLC percutaneous biopsy was subcutaneously inoculated into the flank of non-obese diabetic/severe combined immunodeficiency (NOD/SCID) female mice (PDTX F1) and allowed to reach 500 mm3 volume. Then, the tumors were re-transplanted into Balb/c nude mice and liver metastasis was confirmed (PDTX F2), which were further assigned into doxorubicin (DOX), docetaxel (DTX), and non-treatment control group. H&E staining and Keratin 20 (CK20) staining were applied to determine the consistency of PDTX models and primary tumors. Tumor growth curve, body weight, and the expression of p65 nuclear factor (NF)-κB and the secretion of interferon (IFN)-γ were investigated. The successive transplant procedure can induce the NSCLC-liver metastasis PDTX model, and morphological and structural characteristics of PDTX models (F2) were in accordance with primary tumors. DOX and DTX could delay tumor growth, activate the NF-κB pathway, and promote IFN-γ secretion in the PDTX models. The NSCLC-liver metastasis PDTX model is established and provides a powerful mean to assess chemotherapeutic efficacy.

scholarly journals Identifying Cross-Scale Associations between Radiomic and Pathomic Signatures of Non-Small Cell Lung Cancer Subtypes: Preliminary Results

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3663
Author(s):  
Charlems Alvarez-Jimenez ◽  
Alvaro A. Sandino ◽  
Prateek Prasanna ◽  
Amit Gupta ◽  
Satish E. Viswanath ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Density ◽  
Squamous Cell ◽  
Cell Lung Cancer ◽  
Ct Images ◽  
Small Cell ◽  
Small Cell Lung ◽  
Cancer Subtypes ◽  
Initial Results

(1) Background: Despite the complementarity between radiology and histopathology, both from a diagnostic and a prognostic perspective, quantitative analyses of these modalities are usually performed in disconnected silos. This work presents initial results for differentiating two major non-small cell lung cancer (NSCLC) subtypes by exploring cross-scale associations between Computed Tomography (CT) images and corresponding digitized pathology images. (2) Methods: The analysis comprised three phases, (i) a multi-resolution cell density quantification to identify discriminant pathomic patterns for differentiating adenocarcinoma (ADC) and squamous cell carcinoma (SCC), (ii) radiomic characterization of CT images by using Haralick descriptors to quantify tumor textural heterogeneity as represented by gray-level co-occurrences to discriminate the two pathological subtypes, and (iii) quantitative correlation analysis between the multi-modal features to identify potential associations between them. This analysis was carried out using two publicly available digitized pathology databases (117 cases from TCGA and 54 cases from CPTAC) and a public radiological collection of CT images (101 cases from NSCLC-R). (3) Results: The top-ranked cell density pathomic features from the histopathology analysis were correlation, contrast, homogeneity, sum of entropy and difference of variance; which yielded a cross-validated AUC of 0.72 ± 0.02 on the training set (CPTAC) and hold-out validation AUC of 0.77 on the testing set (TCGA). Top-ranked co-occurrence radiomic features within NSCLC-R were contrast, correlation and sum of entropy which yielded a cross-validated AUC of 0.72 ± 0.01. Preliminary but significant cross-scale associations were identified between cell density statistics and CT intensity values using matched specimens available in the TCGA cohort, which were used to significantly improve the overall discriminatory performance of radiomic features in differentiating NSCLC subtypes (AUC = 0.78 ± 0.01). (4) Conclusions: Initial results suggest that cross-scale associations may exist between digital pathology and CT imaging which can be used to identify relevant radiomic and histopathology features to accurately distinguish lung adenocarcinomas from squamous cell carcinomas.

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