scholarly journals IL‐10 derived from M2 macrophage promotes cancer stemness via JAK1/STAT1/NF‐κB/Notch1 pathway in non‐small cell lung cancer

2019 ◽  
Vol 145 (4) ◽  
pp. 1099-1110 ◽  
Author(s):  
Li Yang ◽  
Ying Dong ◽  
Yanjun Li ◽  
Dong Wang ◽  
Shasha Liu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
M2 Macrophage ◽  
Small Cell Lung ◽  
Cancer Stemness

scholarly journals Characterization of Tumor-Associated Macrophages and the Immune Microenvironment in Limited-Stage Neuroendocrine-High and -Low Small Cell Lung Cancer

Biology ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 502
Author(s):  
David Dora ◽  
Christopher Rivard ◽  
Hui Yu ◽  
Shivaun Lueke Pickard ◽  
Viktoria Laszlo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Cell Counting ◽  
M2 Macrophage ◽  
Strong Positive Correlation ◽  
Small Cell Lung ◽  
Limited Stage ◽  
Macrophage Marker

This study aims to characterize tumor-infiltrating macrophages (TAMs), myeloid-derived suppressor cells (MDSC), and the related molecular milieu regulating anti-tumor immunity in limited-stage neuroendocrine (NE)-high and NE-low small cell lung cancer. Primary tumors and matched lymph node (LN) metastases of 32 resected, early-stage SCLC patients were analyzed by immunohistochemistry (IHC) with antibodies against pan-macrophage marker CD68, M2-macrophage marker CD163, and MDSC marker CD33. Area-adjusted cell counting on TMAs showed that TAMs are the most abundant cell type in the TME, and their number in tumor nests exceeds the number of CD3 + T-cells (64% vs. 38% in NE-low and 71% vs. 18% in NE-high). Furthermore, the ratio of CD163-expressing M2-polarized TAMs in tumor nests was significantly higher in NE-low vs. NE-high tumors (70% vs. 31%). TAM density shows a strong positive correlation with CD45 and CD3 in tumor nests, but not in the stroma. fGSEA analysis on a targeted RNAseq oncological panel of 2560 genes showed that NE-high tumors exhibited increased enrichment in pathways related to cell proliferation, whereas in NE-low tumors, immune response pathways were significantly upregulated. Interestingly, we identified a subset of NE-high tumors representing an immune-oasis phenotype, but with a different gene expression profile compared to NE-low tumors. In contrast, we found that a limited subgroup of NE-low tumors is immune-deserted and express distinct cellular pathways from NE-high tumors. Furthermore, we identified potential molecular targets based on our expression data in NE-low and immune-oasis tumor subsets, including CD70, ANXA1, ITGB6, TP63, IFI27, YBX3 and CXCR2.

A phase Ib/II study of cancer stemness inhibitor napabucasin (BB608) combined with weekly paclitaxel in advanced non-small cell lung cancer.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. 9093-9093 ◽  
Author(s):  
Carlos Becerra ◽  
Alexander I. Spira ◽  
Paul R. Conkling ◽  
Stephen Lane Richey ◽  
Wahid Tewfik Hanna ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Weekly Paclitaxel ◽  
Small Cell Lung ◽  
Cancer Stemness ◽  
Phase Ib

scholarly journals IL-2 stromal signatures dissect immunotherapy response groups in non-small cell lung cancer (NSCLC)

2021 ◽  
Author(s):  
James Monkman ◽  
Honesty Kim ◽  
Aaron Mayer ◽  
Ahmed Mehdi ◽  
Nicholas Matigian ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Checkpoint Inhibitors ◽  
Tumour Microenvironment ◽  
Small Cell ◽  
M2 Macrophage ◽  
Mrna Levels ◽  
Small Cell Lung ◽  
Stromal Activation

Introduction Immunotherapies, such as immune checkpoint inhibitors (ICI) have shown durable benefit in a subset of non-small cell lung cancer (NSCLC) patients. The mechanisms for this are not fully understood, however the composition and activation status of the cellular milieu contained within the tumour microenvironment (TME) is becomingly increasingly recognised as a driving factor in treatment-refractory disease. Methods Here, we employed multiplex IHC (mIHC), and digital spatial profiling (DSP) to capture the targeted immune proteome and transcriptome of tumour and TME compartments of pre-treatment samples from a 2nd line NSCLC ICI-treated cohort (n=41 patients; n=25 responders, n=16 non-responders). Results We demonstrate by mIHC that the interaction of CD68+ macrophages with PD1+, FoxP3+ cells is significantly enriched in ICI refractory tumours (p=0.012). Our study revealed that patients sensitive to ICI therapy expressed higher levels of IL2 receptor alpha (CD25, p=0.028) within the tumour compartments, which corresponded with the increased expression of IL2 mRNA (p=0.001) within their stroma, indicative of key conditions for ICI efficacy prior to treatment. IL2 mRNA levels within the stroma positively correlated with the expression of pro-apoptotic markers cleaved caspase 9 (p=2e-5) and BAD (p=5.5e-4) and negatively correlated with levels of memory T cells (CD45RO) (p=7e-4). Immuno-inhibitory markers CTLA-4 (p=0.021) and IDO-1 (p=0.023) were also supressed in ICI-responsive patients. Of note, tumour CD44 (p=0.02) was depleted in the response group and corresponded inversely with significantly higher stromal expression of its ligand SPP1 (osteopontin, p=0.008). Analysis of differentially expressed transcripts indicated the potential inhibition of stromal interferon-gamma (IFNγ) activity, as well as estrogen-receptor and Wnt-1 signalling activity within the tumour cells of ICI responsive patients. Cox survival analysis indicated tumour CD44 expression was associated with poorer prognosis (HR=1.61, p=0.01), consistent with its depletion in ICI sensitive patients. Similarly, stromal CTLA-4 (HR=1.78, p=0.003) and MDSC/M2 macrophage marker ARG1 (HR=2.37, p=0.01) were associated with poorer outcome while levels of apoptotic marker BAD (HR=0.5, p=0.01) appeared protective. Interestingly, stromal mRNA for E-selectin (HR=652, p=0.001), CCL17 (HR=70, p=0.006) and MTOR (HR=1065, p=0.008) were highly associated with poorer outcome, indicating pro-tumourigenic features in the tumour microenvironment that may facilitate ICI resistance. Conclusions Through multi-modal approaches, we have dissected the characteristics of NSCLC and provide evidence for the role of IL2 and stromal activation by osteopontin in the efficacy of current generations of ICI therapy. The enrichment of SPP1 in the stroma of ICI sensitive patients in our data is a novel finding, indicative of stromal activation that may aid immune cell survival and activity despite no clear association with increased levels of immune infiltrate.

Ubiquitin-protein ligase E3C maintains non-small-cell lung cancer stemness by targeting AHNAK-p53 complex

2019 ◽  
Vol 443 ◽  
pp. 125-134 ◽  
Author(s):  
Jie Gu ◽  
Wei Mao ◽  
Wenjia Ren ◽  
Fengkai Xu ◽  
Qiaoliang Zhu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Cancer Stemness ◽  
Ubiquitin Protein Ligase

scholarly journals M2 macrophage infiltration into tumor islets leads to poor prognosis in non-small-cell lung cancer

2019 ◽  
Vol Volume 11 ◽  
pp. 6125-6138 ◽  
Author(s):  
Lili Cao ◽  
Xiaofang Che ◽  
Xueshan Qiu ◽  
Zhi Li ◽  
Bowen Yang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Poor Prognosis ◽  
Small Cell ◽  
Macrophage Infiltration ◽  
M2 Macrophage ◽  
Small Cell Lung

scholarly journals EGFR-AS1/HIF2A regulates the expression of FOXP3 to impact the cancer stemness of smoking-related non-small cell lung cancer

2019 ◽  
Vol 11 ◽  
pp. 175883591985522 ◽  
Author(s):  
Haolong Qi ◽  
Shanshan Wang ◽  
Juekun Wu ◽  
Shucai Yang ◽  
Steven Gray ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cancer Cell ◽  
Cell Lung Cancer ◽  
Foxp3 Expression ◽  
Small Cell ◽  
Nsclc Cell ◽  
Lung Cancer Cell ◽  
Small Cell Lung ◽  
Cancer Stemness

Background: Early data showed that FOXP3 could induce epithelial-mesenchymal transition by stimulating the Wnt/β-catenin signaling pathway in non-small cell lung cancer (NSCLC). However, how the expression of FOXP3 is regulated in NSCLC remains unknown. We thus explored the impacts of the long noncoding RNA EGFR antisense RNA 1 (EGFR-AS1) and hypoxia-inducible factor-2A (HIF2A) on FOXP3 expression and the cancer stemness of NSCLC. Methods: Lung tissues samples from 87 patients with NSCLC and two NSCLC cell lines were used in this study. The regulation of FOXP3 and lung cancer cell stemness by EGFR-AS1 and HIF2A was determined at molecular levels in NSCLC tissue samples and cultured cells in the presence/absence of the smoking carcinogen, 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) (also known as nicotine-derived nitrosamine ketone). The results were confirmed in tumor xenograft models. Results: We found that NNK decreased the expression of EGFR-AS1 in the long term, but increased the expression of HIF2A and FOXP3 to stimulate lung cancer cell stemness. EGFR-AS1 significantly inhibited FOXP3 expression and NSCLC cell stemness, whereas HIF2A obviously promoted both. The enhancement of lung cancer stemness by FOXP3 was, at least partially, via stimulating Notch1, as the inhibition of Notch1 could markedly diminish the effect of FOXP3. Conclusions: FOXP3, the expression of which is under the fine control of EGFR-AS1, is a critical molecule that promotes NSCLC cancer cell stemness through stimulating the Notch1 pathway.

Sign in / Sign up

Export Citation Format

Share Document