Relationship Between the Invasion of Lymphocytes and Cytokines in the Tumor Microenvironment and the Interval After Single Brachytherapy Hypofractionated Rradiotherapy and Conventional Fractionation Radiotherapy in Non-Small Cell Lung Cancer

Abstract Background Lymphocytes and cytokines in tumor microenvironment are the key to immunotherapy, The effect of brachytherapy on tumor microenvironment is not clear. The aim of our study was to analyze the relationship between the invasion of lymphocytes and cytokines in the tumor microenvironment and the interval after single brachytherapy hypofractionated radiotherapy (SBHFRT) and conventional fractionation radiotherapy (CFRT) in non-small cell lung cancer (NSCLC). Methods Lewis tumor-bearing mice were randomly divided into control, CFRT and SBHFRT groups. On the days 7 and 14 after radiation, the expression rates of CD4+, CD8+, Foxp3+, and CD86 + cells and levels of Ki-67 + protein were detected by immunohistochemical analysis, and the tumor necrosis rate was calculated. Following this, interleukin-10 (IL-10), IL-12, and interferon-γ (INF-γ) levels were detected by enzyme-linked immunosorbent assay. The apoptosis rate was evaluated via flow cytometry. The tumor volume and tumor growth inhibition rate (TGIR) were calculated on day 14. Tumor metabolism was assessed via micro 18F-FDG positron emission tomography/computer tomography. Results The tumor volume in the SBHFRT group reduced by 22.0% and TGIR increased by 92.2% (P < 0.05). Further, on days 7 and 14 after radiation, tumor metabolism, Ki-67 + and Foxp3 + expression rates, and IL-10 levels were lower and tumor necrosis and apoptosis rates; CD86+, CD4+, and CD8 + expression rates; and IL-12 and INF-γ levels were higher in SBHFRT group than in the CFRT group, particularly on day 7. Conclusion SBHFRT could lead to more accumulation of dendritic cells and anti-tumor lymphocytes and cytokines in the tumor tissue, and further reduce the aggregation of immunosuppressive lymphocytes and cytokines in the tumor tissue compared with CFRT, and the difference was the most obvious was day 7 after radiation. Hypofractionated radiotherapy combined with immunotherapy may be better for treating NSCLC, as observed on day 7 after radiation.

Download Full-text

Relationship between the invasion of lymphocytes and cytokines in the tumor microenvironment and the interval after single brachytherapy hypofractionated radiotherapy and conventional fractionation radiotherapy in non-small cell lung Cancer

BMC Cancer ◽

10.1186/s12885-020-07403-1 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Lin Li ◽

Hong Cheng Yue ◽

Yun Wei Han ◽

Wei Liu ◽

Liang Geng Xiong ◽

...

Keyword(s):

Lung Cancer ◽

Tumor Microenvironment ◽

Tumor Necrosis ◽

Tumor Volume ◽

Small Cell ◽

Small Cell Lung ◽

Ki 67 ◽

Expression Levels ◽

Conventional Fractionation ◽

Ifn Γ

Abstract Background The effect of brachytherapy on lymphocytes and cytokines in the tumor microenvironment is unclear. This study aimed to analyze the relationship between the invasion of lymphocytes and cytokines in the tumor microenvironment and the interval after single brachytherapy hypofractionated radiotherapy (SBHFRT) and conventional fractionation radiotherapy (CFRT) in non-small cell lung cancer (NSCLC). Methods Lewis tumor-bearing mice were randomly divided into control, CFRT, and SBHFRT groups. On days 7 and 14 after radiation, the expression levels of CD86+, CD4+, CD8+, and Foxp3+ cells, and levels of Ki-67+ protein were detected by immunohistochemistry, and the tumor necrosis rate was calculated. Following this, the levels of interleukin-10 (IL-10), IL-12, and interferon-γ (IFN-γ) were detected by enzyme-linked immunosorbent assay. The apoptosis rate was evaluated via flow cytometry. The tumor volume and tumor growth inhibition rate (TGIR) were calculated on day 14. Tumor metabolism was assessed via 18F-FDG micropositron emission tomography/computer tomography. Results The tumor volume reduced by 22.0% and TGIR increased by 92.2% (p < 0.05) in the SBHFRT group. Further, on days 7 and 14 after radiation, tumor metabolism, Ki-67+ and Foxp3+ expression levels, and IL-10 levels were lower, and tumor necrosis and apoptosis rates; CD86+, CD4+, and CD8+ expression levels; and IL-12 and IFN-γ levels were higher in the SBHFRT group than in the CFRT group, particularly on day 7. Conclusion SBHFRT could lead to more accumulation of dendritic cells, anti-tumor lymphocytes, and cytokines, and further reduce the aggregation of immunosuppressive lymphocytes and cytokines in the tumor microenvironment compared with CFRT, and the difference was the most obvious on day 7 after radiation. The clinical significance of the findings remains to be further verified.

Download Full-text

INFLUENCE OF SMOKING ON THE EXPRESSION OF p53 AND Ki-67 PROTEINS IN PATIENTS WITH NON-SMALL CELL LUNG CANCER

RISK FACTORS OF FOOD CHAIN 2017 PROCEEDIINGS OF XVIII INTERNATIONAL SCIENTIFIC CONFERENCE ◽

10.24917/9788380840973.14 ◽

2017 ◽

Author(s):

P. Rogoziński ◽

◽

Łukasz Binkowski ◽

M. Semla ◽

M. Kucharzewski ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Small Cell Lung ◽

Ki 67

Download Full-text

Association between serum tumor markers and metabolic tumor volume or total lesion glycolysis in patients with recurrent small cell lung cancer

Oncology Letters ◽

10.3892/ol.2015.3673 ◽

2015 ◽

Vol 10 (5) ◽

pp. 3123-3128 ◽

Cited By ~ 2

Author(s):

PENGYUE SHI ◽

XUE MENG ◽

MENGMENG NI ◽

XINDONG SUN ◽

LIGANG XING ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Tumor Markers ◽

Cell Lung Cancer ◽

Tumor Volume ◽

Metabolic Tumor Volume ◽

Total Lesion Glycolysis ◽

Small Cell ◽

Small Cell Lung ◽

Serum Tumor Markers

Download Full-text

Tumor Volume Decrease at 8 Weeks Is Associated with Longer Survival in EGFR-Mutant Advanced Non–Small-Cell Lung Cancer Patients Treated with EGFR TKI

Journal of Thoracic Oncology ◽

10.1097/jto.0b013e318294c909 ◽

2013 ◽

Vol 8 (8) ◽

pp. 1059-1068 ◽

Cited By ~ 33

Author(s):

Mizuki Nishino ◽

Suzanne E. Dahlberg ◽

Stephanie Cardarella ◽

David M. Jackman ◽

Michael S. Rabin ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cancer Patients ◽

Tumor Volume ◽

Small Cell ◽

Small Cell Lung ◽

Lung Cancer Patients ◽

Egfr Mutant ◽

Egfr Tki ◽

Volume Decrease

Download Full-text

921 Comparison of PI3K/AKT/mTOR pathway profiles amongst three immune phenotypes classified by artificial intelligence-powered H&E analyzer in non-small cell lung cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.921 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A966-A966

Author(s):

Hyung-Gyo Cho ◽

Grace Lee ◽

Hye Sung Kim ◽

Sanghoon Song ◽

Kyunghyun Paeng ◽

...

Keyword(s):

Lung Cancer ◽

Tumor Microenvironment ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Mtor Pathway ◽

Small Cell Lung ◽

Gene Set ◽

Mtorc1 Signaling ◽

Immune Phenotypes

BackgroundThe phosphatidylinositol 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway plays a significant role in both tumorigenesis and progression of disease in non-small cell lung cancer (NSCLC).1 Increased activation of the pathway, whether in tumor or immune cells, results in an immunosuppressive tumor microenvironment.2 Therefore, we looked into how this pathway differs in three distinct NSCLC immune phenotypes.MethodsLunit SCOPE IO (Lunit, Seoul, Republic of Korea), a deep learning-based hematoxylin and eosin (H&E) image analytics tool, identifies lymphocytes and quantifies lymphocyte density within the cancer epithelium (CE-Lym), stroma (CS-Lym), and combined area (C-Lym). We applied Lunit-SCOPE IO to H&E-stained tissue images of 965 NSCLC samples from The Cancer Genome Atlas (TCGA). Tumors in the lowest tertile of C-Lym were labeled as immune-desert, and the remaining tumors were classified as inflamed and immune-excluded according to the median of the ratio of CE-Lym to CS-Lym.Utilizing RNA-sequencing data from TCGA, gene set enrichment analysis (GSEA) was conducted to analyze the differences in mTORC1 and PI3K/Akt/mTOR signaling between the subtypes.3 We obtained mutational data related to the PI3K/Akt/mTOR pathway from cBioPortal to compare the ratio of functional mutations between the immune phenotypes.4ResultsThe mTORC1 signaling gene set was consistently enriched in immune-excluded, whether compared to inflamed (padj < 0.01, normalized enrichment score [NES]: 2.3) or immune-desert (padj < 0.01, NES: 1.6). However, PI3K/Akt/mTOR signaling gene set enrichment did not show statistically significant differences between the immune phenotypes.Within the three immune phenotypes, we analyzed three functional mutations: PIK3CA, PTEN, and Akt1 (figure 1). Of the total 112 samples showing the functional mutations of the PI3K/Akt/mTOR pathway, 53 were immune-excluded, 31 inflamed, and 28 immune-desert. The relation between mutation frequency and the immune subtypes was significant (X2 (2) = 11.1979, p < .01). The immune-excluded was more likely than the other subtypes to have functional PI3K/Akt/mTOR mutations.Abstract 921 Figure 1The landscape of functional mutation and immune phenotypes regarding PI3K/Akt/mTOR pathwayConclusionsThe three tissue phenomic subtypes showed different PI3K/Akt/mTOR pathway profiles, with immune-excluded having the most mutation samples and the greatest enhancement of mTORC1 signaling gene set. Likewise, tissue H&E based tumor microenvironment classification by Lunit SCOPE IO can be applied to other hallmark pathways and tumor types, and such further investigation of the tumor microenvironment can provide insights into novel therapeutic avenues.ReferencesTan AC. Targeting the PI3K/Akt/mTOR pathway in non-small cell lung cancer (NSCLC). Thorac Cancer 2020;11(3):511–8.O’Donnell JS, Massi D, Teng MWL, Mandala M. PI3K-AKT-mTOR inhibition in cancer immunotherapy, redux. Semin Cancer Biol 2018;48:91–103.Liberzon A, Birger C, Thorvaldsdóttir H, Ghandi M, Mesirov JP, Tamayo P. The molecular signatures database hallmark gene set collection. Cell Systems 2015;1(6):417–25.Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2012;2(5):401–4.

Download Full-text

Circadian rhythm-associated clinical relevance and Tumor Microenvironment of Non-small Cell Lung Cancer

Journal of Cancer ◽

10.7150/jca.52454 ◽

2021 ◽

Vol 12 (9) ◽

pp. 2582-2597

Author(s):

Ming Li ◽

Zhencong Chen ◽

Tian Jiang ◽

Xiaodong Yang ◽

Yajing Du ◽

...

Keyword(s):

Lung Cancer ◽

Circadian Rhythm ◽

Tumor Microenvironment ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Clinical Relevance ◽

Small Cell ◽

Small Cell Lung

Download Full-text

Natural Killer Cells and Dendritic Cells: Expanding Clinical Relevance in the Non-Small Cell Lung Cancer (NSCLC) Tumor Microenvironment

Cancers ◽

10.3390/cancers13164037 ◽

2021 ◽

Vol 13 (16) ◽

pp. 4037

Author(s):

Pankaj Ahluwalia ◽

Meenakshi Ahluwalia ◽

Ashis K. Mondal ◽

Nikhil S. Sahajpal ◽

Vamsi Kota ◽

...

Keyword(s):

Lung Cancer ◽

Dendritic Cells ◽

Tumor Microenvironment ◽

Small Cell Lung Cancer ◽

Nk Cells ◽

Natural Killer ◽

Cell Lung Cancer ◽

Immune Cells ◽

Small Cell ◽

Small Cell Lung

Non-small cell lung cancer (NSCLC) is a major subtype of lung cancer that accounts for almost 85% of lung cancer cases worldwide. Although recent advances in chemotherapy, radiotherapy, and immunotherapy have helped in the clinical management of these patients, the survival rate in advanced stages remains dismal. Furthermore, there is a critical lack of accurate prognostic and stratification markers for emerging immunotherapies. To harness immune response modalities for therapeutic benefits, a detailed understanding of the immune cells in the complex tumor microenvironment (TME) is required. Among the diverse immune cells, natural killer (NK cells) and dendritic cells (DCs) have generated tremendous interest in the scientific community. NK cells play a critical role in tumor immunosurveillance by directly killing malignant cells. DCs link innate and adaptive immune systems by cross-presenting the antigens to T cells. The presence of an immunosuppressive milieu in tumors can lead to inactivation and poor functioning of NK cells and DCs, which results in an adverse outcome for many cancer patients, including those with NSCLC. Recently, clinical intervention using modified NK cells and DCs have shown encouraging response in advanced NSCLC patients. Herein, we will discuss prognostic and predictive aspects of NK cells and DC cells with an emphasis on NSCLC. Additionally, the discussion will extend to potential strategies that seek to enhance the anti-tumor functionality of NK cells and DCs.

Download Full-text