Mechanism of Fuzheng Kang’ai Formula (扶正抗癌方) Regulating Tumor Microenvironment in Non-Small Cell Lung Cancer

Author(s):  
Yun-ling Tian ◽  
Song-bo Fu ◽  
Bo Li ◽  
Ling-yan Yuan ◽  
Zhi-tong Bing
2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A966-A966
Author(s):  
Hyung-Gyo Cho ◽  
Grace Lee ◽  
Hye Sung Kim ◽  
Sanghoon Song ◽  
Kyunghyun Paeng ◽  
...  

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.


2021 ◽  
Vol 12 (9) ◽  
pp. 2582-2597
Author(s):  
Ming Li ◽  
Zhencong Chen ◽  
Tian Jiang ◽  
Xiaodong Yang ◽  
Yajing Du ◽  
...  

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4037
Author(s):  
Pankaj Ahluwalia ◽  
Meenakshi Ahluwalia ◽  
Ashis K. Mondal ◽  
Nikhil S. Sahajpal ◽  
Vamsi Kota ◽  
...  

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.


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