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Author Spotlight: Enhancing Multicolor Fluorescence Localization in Lung Carcinoma Sample
Published on: November 21, 2023
Molecular subtypes of lung adenocarcinoma present distinct immune tumor microenvironments
Hironori Fukuda1,2, Kosuke Arai1,3, Hideaki Mizuno4
1Department of Immune Medicine, National Cancer Center Research Institute, Tokyo, Japan.
Abstract:
Overcoming resistance to immune checkpoint inhibitors is an important issue in patients with non-small-cell lung cancer (NSCLC). Transcriptome analysis shows that adenocarcinoma can be divided into three molecular subtypes: terminal respiratory unit (TRU), proximal proliferative (PP), and proximal inflammatory (PI), and squamous cell carcinoma (LUSQ) into four. However, the immunological characteristics of these subtypes are not fully understood. In this study, we investigated the immune landscape of NSCLC tissues in molecular subtypes using a multi-omics dataset, including tumor-infiltrating leukocytes (TILs) analyzed using flow cytometry, RNA sequences, whole exome sequences, metabolomic analysis, and clinicopathologic findings. In the PI subtype, the number of TILs increased and the immune response in the tumor microenvironment (TME) was activated, as indicated by high levels of tertiary lymphoid structures, and high cytotoxic marker levels. Patient prognosis was worse in the PP subtype than in other adenocarcinoma subtypes. Glucose transporter 1 (GLUT1) expression levels were upregulated and lactate accumulated in the TME of the PP subtype. This could lead to the formation of an immunosuppressive TME, including the inactivation of antigen-presenting cells. The TRU subtype had low biological malignancy and "cold" tumor-immune phenotypes. Squamous cell carcinoma (LUSQ) did not show distinct immunological characteristics in its respective subtypes. Elucidation of the immune characteristics of molecular subtypes could lead to the development of personalized immune therapy for lung cancer. Immune checkpoint inhibitors could be an effective treatment for the PI subtype. Glycolysis is a potential target for converting an immunosuppressive TME into an antitumorigenic TME in the PP subtype.
Insights
Understanding non-small cell lung cancer (NSCLC) molecular subtypes reveals distinct immune landscapes. The proximal inflammatory (PI) subtype shows activated immunity, while the proximal proliferative (PP) subtype exhibits an immunosuppressive microenvironment, guiding personalized immunotherapy strategies.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Non-small cell lung cancer (NSCLC) exhibits molecular heterogeneity, impacting treatment response.
- Understanding the immune microenvironment (TME) of NSCLC subtypes is crucial for overcoming resistance to immune checkpoint inhibitors.
- Current knowledge of immunological characteristics across NSCLC molecular subtypes remains incomplete.
Purpose of the Study:
- To investigate the immune landscape of NSCLC molecular subtypes using a multi-omics approach.
- To correlate molecular subtypes with immune cell infiltration, TME features, and clinical outcomes.
- To identify potential therapeutic targets for personalized immunotherapy in NSCLC.
Main Methods:
- Multi-omics analysis of NSCLC tissues, including flow cytometry for tumor-infiltrating leukocytes (TILs), RNA sequencing, whole exome sequencing, and metabolomics.
- Correlation of molecular subtypes (TRU, PP, PI for adenocarcinoma; LUSQ for squamous cell carcinoma) with immunological and clinicopathological data.
- Assessment of tertiary lymphoid structures, cytotoxic markers, glucose transporter 1 (GLUT1) expression, and lactate levels.
Main Results:
- The proximal inflammatory (PI) subtype demonstrated increased TILs, activated immune responses, and high cytotoxic markers.
- The proximal proliferative (PP) subtype showed poorer prognosis, elevated GLUT1 expression, and lactate accumulation, suggesting an immunosuppressive TME.
- The terminal respiratory unit (TRU) subtype exhibited low malignancy and a 'cold' immune phenotype; squamous cell carcinoma (LUSQ) subtypes lacked distinct immunological profiles.
Conclusions:
- Molecular subtypes of NSCLC possess distinct immune landscapes, influencing patient prognosis and treatment response.
- The PI subtype may benefit from immune checkpoint inhibitors due to its activated immune TME.
- Targeting glycolysis in the PP subtype could potentially convert the immunosuppressive TME to an antitumorigenic one for improved NSCLC therapy.
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