Small cell lung cancer tumors and preclinical models display heterogeneity of neuroendocrine phenotypes

Zhang, Wei; Girard, Luc; Zhang, Yu An; Haruki, Tomohiro; Papari-Zareei, Mahboubeh; Stastny, Victor; Ghayee, Hans K.; Pacák, Karel; Oliver, Trudy G.; Minna, John D.; Gazdar, Adi F.

doi:10.21037/tlcr.2018.02.02

Cited by 212 publications

(291 citation statements)

References 70 publications

Supporting

Mentioning

264

Contrasting

Order By: Relevance

“…Next, we compared in situ the quantitative and qualitative extent of the immunological microenvironment of SCLC tumors according to NE-low and NE-high subtypes. In line with previously published in vitro data, our results confirm that NE-low tumors are significantly more infiltrated by immune cells, primarily by CD8+ effector T cells (Zhang et al, 2018).…”

Section: I and J)supporting

confidence: 92%

“…Our group on the same TMA sets clustered NE-high and NE-low SCLC subsets (Lohinai et al, 2020) based on the top RNA genes associated with NE differentiation (Gazdar 2018;Zhang et al, 2018). Furthermore, the latest preclinical studies suggest that, compared to the NE-high, the NE-low subtype is more likely to respond to immunotherapy due to its 'immune oasis' phenotype, emphasizing the necessity and importance of molecular and in situ immunological characterization before the assessment of therapies to this type of recalcitrant cancer (Gazdar 2018;Zhang et al, 2018;Ito et al, 2016).…”

Section: I and J)mentioning

confidence: 99%

See 1 more Smart Citation

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

Dóra

Rivard

et al. 2020

Preprint

View full text Add to dashboard Cite

The authors thank the patients and the clinical teams involved. We thank Leslie Rozeboom for her assistance in creating TMA blocks. 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 3 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 NEhigh) 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.

show abstract

Section: I and J)supporting

confidence: 92%

Section: I and J)mentioning

confidence: 99%

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

Dóra

Rivard

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…On the other hand, a negative correlation was observed between Lac/Glc and ssGSEA scores derived from gene sets related to neuronal processes, which tend to be expressed in cell lines with neuroendocrine differentiation (lonescu et al, 2007). We therefore derived neuroendocrine scores for our cell lines based on a 50-gene signature (Zhang et al, 2018) and found that cell lines with high neuroendocrine scores are invariably low in Lac/Glc ( Figure 1F ). Altogether these data indicate that hypoxia gene sets correlate with glycolytic metabolism even when cells are cultured in normoxia, and that cell lines with neuroendocrine-like gene expression signatures release relatively little lactate per glucose consumed.…”

Section: Resultsmentioning

confidence: 99%

Metabolic Diversity in Human Non-Small Cell Lung Cancer Cells

Chen

Cai

Huffman

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

SummaryIntermediary metabolism in cancer cells is regulated by diverse cell-autonomous processes including signal transduction and gene expression patterns arising from specific oncogenotypes and cell lineages. Although it is well established that metabolic reprogramming is a hallmark of cancer, we lack a full view of the diversity of metabolic programs in cancer cells and an unbiased assessment of the associations between metabolic pathway preferences and other cell-autonomous processes. Here we quantified over 100 metabolic features, mostly from 13C enrichment of molecules from central carbon metabolism, in over 80 non-small cell lung cancer (NSCLC) cell lines cultured under identical conditions. Because these cell lines were extensively annotated for oncogenotype, gene expression, protein expression and therapeutic sensitivity, the resulting database enables the user to uncover new relationships between metabolism and these orthogonal processes.

show abstract

“…Distinguishing SCLC subtypes by expression of neuroendocrine genes such as CHGA and GRP identifies two groups: neuroendocrine high (NE high ; ∼80%) and neuroendocrine low (NE low ; ∼20%). Within the NE high group, the basic helix-loop-helix (bHLH) transcription factor ASCL1 is considered a master regulator for a majority of these SCLC, while a related bHLH factor, NEUROD1, characterizes a smaller subset with intermediate neuroendocrine characteristics (Osborne et al 2013;George et al 2015;Borromeo et al 2016;Zhang et al 2018). In contrast, most NE low SCLCs do not express ASCL1 or NEUROD1.…”

mentioning

confidence: 99%

Identifying a missing lineage driver in a subset of lung neuroendocrine tumors

2018

Self Cite

View full text Add to dashboard Cite

Tumor heterogeneity of a primary histologic cancer type has major implications for cancer research and therapeutics. An important and understudied aspect of this heterogeneity is the role of transcription factors that serve as "lineage oncogenes" in a tumor type. A demonstration that different subgroups have distinct dependencies on lineage-specific transcription factors is highlighted in a relatively homogenous cancer type: the pulmonary neuroendocrine cancer small cell lung carcinoma (SCLC). Identification of these factors is providing new insights into the origin of the heterogeneity and subtype-specific vulnerabilities in SCLC and provides a template for studying heterogeneity in other cancer types.

show abstract

Small cell lung cancer tumors and preclinical models display heterogeneity of neuroendocrine phenotypes

Cited by 212 publications

References 70 publications

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

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

Metabolic Diversity in Human Non-Small Cell Lung Cancer Cells

Identifying a missing lineage driver in a subset of lung neuroendocrine tumors

Contact Info

Product

Resources

About