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Deciphering the tumor microenvironment cell-infiltrating landscape reveals microenvironment subtypes and therapeutic
Hao Chen1, Tongchao Zhang1, Yuan Zhang1
1Clinical Research Center of Shandong University, Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, Shandong, China.
Abstract:
Recent studies highlighted the clinicopathologic importance of the tumor microenvironment (TME) in delineating molecular attributes and therapeutic potentials. However, the overall TME cell infiltration landscape in nonsquamous non-small cell lung cancer (NSCLC) has not been comprehensively characterized. In this study, we used consensus non-negative matrix factorization molecular subtyping to determine TME cell infiltration patterns and identified 3 TME clusters (TME-C1, -C2, -C3) characterized by distinct clinicopathologic features, infiltrating cells, and biological processes. Proteomics analyses revealed that cyclic GMP-AMP-stimulator of interferon genes immune signaling-mediated protein and phosphorylation levels were significantly upregulated in inflammation-related TME-C2 clusters. The score extracted from the TME-related signature (TMEsig-score) divided patients with NSCLC into high- and low-score subgroups, where a high score was associated with favorable prognosis and immune infiltration. The genomic landscape revealed that patients with low TMEsig-score harbored more somatic copy number alterations and higher mutation frequency of driver genes involving STK11, KEAP1, SMARCA4, and others. Drug sensitivity analyses suggested that tumors with high TMEsig-score were responsible for favorable clinical response to immune checkpoint inhibitor treatment. In summary, this study highlights that comprehensive recognizing of the TME cell infiltration landscape will contribute to enhancing our understanding of TME immune regulation and promote effectiveness of precision biotherapy strategies.
Insights
Understanding the tumor microenvironment (TME) in nonsquamous non-small cell lung cancer (NSCLC) reveals distinct TME clusters. A high TME signature score correlates with better prognosis and response to immunotherapy.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- The tumor microenvironment (TME) is crucial for understanding cancer biology and treatment.
- Comprehensive characterization of TME cell infiltration in nonsquamous non-small cell lung cancer (NSCLC) is lacking.
Purpose of the Study:
- To define TME cell infiltration patterns in nonsquamous NSCLC.
- To correlate TME characteristics with clinicopathologic features, genomic alterations, and therapeutic response.
Main Methods:
- Consensus non-negative matrix factorization for TME subtyping.
- Proteomics to analyze signaling pathways.
- Genomic profiling and drug sensitivity analysis.
Main Results:
- Identified 3 distinct TME clusters (TME-C1, -C2, -C3) with unique features.
- Upregulation of cGAS-STING pathway in inflammation-related TME-C2 clusters.
- A TME signature score stratified patients, with high scores indicating favorable prognosis, increased immune infiltration, and better response to immune checkpoint inhibitors.
- Low TME signature scores were associated with increased somatic copy number alterations and mutations in driver genes (e.g., STK11, KEAP1, SMARCA4).
Conclusions:
- Characterizing the TME cell infiltration landscape is vital for understanding immune regulation in NSCLC.
- The TME signature score can predict patient prognosis and response to immunotherapy.
- This knowledge can enhance precision biotherapy strategies for NSCLC.
