scholarly journals Tumor-intrinsic response to IFNγ shapes the tumor microenvironment and anti–PD-1 response in NSCLC

2019 ◽  
Vol 2 (3) ◽  
pp. e201900328 ◽  
Author(s):  
Bonnie L Bullock ◽  
Abigail K Kimball ◽  
Joanna M Poczobutt ◽  
Alexander J Neuwelt ◽  
Howard Y Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Microenvironment ◽  
Lewis Lung Carcinoma ◽  
Sequencing Analysis ◽  
Lewis Lung ◽  
Lung Cancer Cell ◽  
Lung Cancer Patients ◽  
T Cell Infiltration ◽  
Basal Expression

Targeting PD-1/PD-L1 is only effective in ∼20% of lung cancer patients, but determinants of this response are poorly defined. We previously observed differential responses of two murine K-Ras–mutant lung cancer cell lines to anti–PD-1 therapy: CMT167 tumors were eliminated, whereas Lewis Lung Carcinoma (LLC) tumors were resistant. The goal of this study was to define mechanism(s) mediating this difference. RNA sequencing analysis of cancer cells recovered from lung tumors revealed that CMT167 cells induced an IFNγ signature that was blunted in LLC cells. Silencing Ifngr1 in CMT167 resulted in tumors resistant to IFNγ and anti–PD-1 therapy. Conversely, LLC cells had high basal expression of SOCS1, an inhibitor of IFNγ. Silencing Socs1 increased response to IFNγ in vitro and sensitized tumors to anti–PD-1. This was associated with a reshaped tumor microenvironment, characterized by enhanced T cell infiltration and enrichment of PD-L1hi myeloid cells. These studies demonstrate that targeted enhancement of tumor-intrinsic IFNγ signaling can induce a cascade of changes associated with increased therapeutic vulnerability.

scholarly journals Tumor-Intrinsic Response to IFNγ Shapes the Tumor Microenvironment and Anti-PD-1 Response in NSCLC

2019 ◽  
Author(s):  
Bonnie L. Bullock ◽  
Abigail K. Kimball ◽  
Joanna M. Poczobutt ◽  
Howard Y. Li ◽  
Jeff W. Kwak ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Rna Seq ◽  
Lung Cancer Cell ◽  
Immunocompetent Mouse ◽  
Lung Cancer Patients ◽  
T Cell Infiltration ◽  
Basal Expression

AbstractTargeting PD-1/ PD-L1 is only effective in ~20% of lung cancer patients, but determinants of this response are poorly defined. We previously observed differential responses of two murine K-Ras lung cancer cell lines to anti-PD-1 therapy: CMT167 tumors were eliminated while LLC tumors were resistant. The goal of this study was to define mechanism(s) mediating this difference. RNA-Seq analysis of cancer cells recovered from lung tumors revealed that CMT167 cells induced an IFNγ signature that was absent in LLC cells. Silencing Ifngr1 in CMT167 resulted in tumors resistant to IFNγ and anti-PD-1 therapy. Conversely, LLC cells had high basal expression of Socs1, an inhibitor of IFNγ. Silencing Socs1 increased response to IFNγ in vitro and sensitized tumors to anti-PD-1. This was associated with a reshaped TME, characterized by enhanced T cell infiltration and enrichment of PD-L1 high myeloid cells. These studies demonstrate that targeted enhancement of tumor-intrinsic IFNγ signaling can induce of cascade of changes associated with increased therapeutic vulnerability.SummaryMechanisms regulating response to anti-PD-1 therapy in lung cancer are not well defined. This study, using orthotopic immunocompetent mouse models of lung cancer, demonstrates that intrinsic sensitivity of cancer cells to IFNγ determines anti-PD-1 responsiveness through alterations in the tumor microenvironment.

scholarly journals Targeting HSP90 Inhibits Proliferation and Induces Apoptosis Through AKT1/ERK Pathway in Lung Cancer

2022 ◽  
Vol 12 ◽  
Author(s):  
Mengyuan Niu ◽  
Bin Zhang ◽  
Li Li ◽  
Zhonglan Su ◽  
Wenyuan Pu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cell ◽  
Lung Tumor ◽  
Hsp90 Inhibitor ◽  
Tumor Xenograft ◽  
Mouse Lung ◽  
Lung Cancer Cell ◽  
Lung Cancer Patients ◽  
Normal Tissues

Lung cancer is one of the most common malignant cancers worldwide. Searching for specific cancer targets and developing efficient therapies with lower toxicity is urgently needed. HPS90 is a key chaperon protein that has multiple client proteins involved in the development of cancer. In this study, we investigated the transcriptional levels of HSP90 isoforms in cancerous and normal tissues of lung cancer patients in multiple datasets. The higher expression of HSP90AA1 in cancer tissues correlated with poorer overall survival was observed. The higher levels of transcription and expression of HSP90AA1 and the activity of AKT1/ERK pathways were confirmed in lung cancer patient tissues. In both human and mouse lung cancer cell lines, knocking down HSP90AA1 promoted cell apoptosis through the inhibition of the pro-survival effect of AKT1 by decreasing the phosphorylation of itself and its downstream factors of mTOR and BAD, as well as downregulating Mcl1, Bcl-xl, and Survivin. The knockdown also suppressed lung cancer cell proliferation by inhibiting ERK activation and downregulating CyclinD1 expression. The treatment of 17-DMAG, an HSP90 inhibitor, recaptured these effects in vitro and inhibited tumor cell growth, and induced apoptosis without obvious side effects in lung tumor xenograft mouse models. This study suggests that targeting HSP90 by 17-DMAG could be a potential therapy for the treatment of lung cancer.

scholarly journals USP9X-mediated KDM4C deubiquitination promotes lung cancer radioresistance by epigenetically inducing TGF-β2 transcription

2021 ◽  
Author(s):  
Xiaohua Jie ◽  
William Pat Fong ◽  
Rui Zhou ◽  
Ye Zhao ◽  
Yingchao Zhao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Affinity Purification ◽  
Smad Signaling ◽  
Lung Cancer Patients ◽  
Lysine Specific Demethylase ◽  
Underlying Mechanisms ◽  
H3k9me3 Level ◽  
Critical Binding

AbstractRadioresistance is regarded as the main barrier to effective radiotherapy in lung cancer. However, the underlying mechanisms of radioresistance remain elusive. Here, we show that lysine-specific demethylase 4C (KDM4C) is overexpressed and correlated with poor prognosis in lung cancer patients. We provide evidence that genetical or pharmacological inhibition of KDM4C impairs tumorigenesis and radioresistance in lung cancer in vitro and in vivo. Moreover, we uncover that KDM4C upregulates TGF-β2 expression by directly reducing H3K9me3 level at the TGF-β2 promoter and then activates Smad/ATM/Chk2 signaling to confer radioresistance in lung cancer. Using tandem affinity purification technology, we further identify deubiquitinase USP9X as a critical binding partner that deubiquitinates and stabilizes KDM4C. More importantly, depletion of USP9X impairs TGF-β2/Smad signaling and radioresistance by destabilizing KDM4C in lung cancer cells. Thus, our findings demonstrate that USP9X-mediated KDM4C deubiquitination activates TGF-β2/Smad signaling to promote radioresistance, suggesting that targeting KDM4C may be a promising radiosensitization strategy in the treatment of lung cancer.

Asian ginseng extract inhibits in vitro and in vivo growth of mouse lewis lung carcinoma via modulation of ERK-p53 and NF-κB signaling

2010 ◽  
Vol 111 (4) ◽  
pp. 899-910 ◽  
Author(s):  
Vincent Kam Wai Wong ◽  
Simon Shiu Fai Cheung ◽  
Ting Li ◽  
Zhi-Hong Jiang ◽  
Jing-Rong Wang ◽  
...  
Keyword(s):  
Lung Carcinoma ◽  
Lewis Lung Carcinoma ◽  
Lewis Lung ◽  
Ginseng Extract ◽  
In Vivo Growth

scholarly journals In vitro secretion of cytokines and prostaglandin-E2by monocytes from lung cancer patients

2001 ◽  
Vol 95 (4) ◽  
pp. 243-245 ◽  
Author(s):  
Y.G. TREJO ◽  
R.H. BORDENAVE ◽  
M. BEVIACQUA ◽  
L.S. RUMI
Keyword(s):  
Lung Cancer ◽  
Cancer Patients ◽  
Lung Cancer Patients

Granulocyte-colony stimulating factor promotes invasion by human lung cancer cell lines in vitro

1996 ◽  
Vol 14 (4) ◽  
pp. 351-357 ◽  
Author(s):  
Xin-Hai Pei ◽  
Yoichi Nakanishi ◽  
Koichi Takayama ◽  
Jun Yatsunami ◽  
Feng Bai ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Lung ◽  
Human Lung Cancer ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Lung Cancer Cell ◽  
Stimulating Factor
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