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Updated: Jul 25, 2025
Evaluation of Tumor-infiltrating Leukocyte Subsets in a Subcutaneous Tumor Model
Published on: April 13, 2015
Tumor-infiltrating Leukocyte Profiling Defines Three Immune Subtypes of NSCLC with Distinct Signaling Pathways and
Kazunori Aoki1, Yukari Nishito2, Noriko Motoi3
1Department of Immune Medicine, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
Abstract:
Resistance to immune checkpoint blockade remains challenging in patients with non-small cell lung cancer (NSCLC). Tumor-infiltrating leukocyte (TIL) quantity, composition, and activation status profoundly influence responsiveness to cancer immunotherapy. This study examined the immune landscape in the NSCLC tumor microenvironment by analyzing TIL profiles of 281 fresh resected NSCLC tissues. Unsupervised clustering based on numbers and percentages of 30 TIL types classified adenocarcinoma (LUAD) and squamous cell carcinoma (LUSQ) into the cold, myeloid cell-dominant, and CD8+ T cell-dominant subtypes. These were significantly correlated with patient prognosis; the myeloid cell subtype had worse outcomes than the others. Integrated genomic and transcriptomic analyses, including RNA sequencing, whole-exome sequencing, T-cell receptor repertoire, and metabolomics of tumor tissue, revealed that immune reaction-related signaling pathways were inactivated, while the glycolysis and K-ras signaling pathways activated in LUAD and LUSQ myeloid cell subtypes. Cases with ALK and ROS1 fusion genes were enriched in the LUAD myeloid subtype, and the frequency of TERT copy-number variations was higher in LUSQ myeloid subtype than in the others. These classifications of NSCLC based on TIL status may be useful for developing personalized immune therapies for NSCLC.
Significance:
The precise TIL profiling classified NSCLC into novel three immune subtypes that correlates with patient outcome, identifying subtype-specific molecular pathways and genomic alterations that should play important roles in constructing subtype-specific immune tumor microenvironments. These classifications of NSCLC based on TIL status are useful for developing personalized immune therapies for NSCLC.
Insights
Tumor-infiltrating leukocyte (TIL) profiling classified non-small cell lung cancer (NSCLC) into three subtypes, with myeloid cell dominance linked to poorer prognosis. This classification aids in developing personalized immunotherapies for NSCLC patients.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Immune checkpoint blockade resistance is a significant challenge in non-small cell lung cancer (NSCLC).
- Tumor-infiltrating leukocyte (TIL) characteristics critically impact responses to cancer immunotherapy.
- Understanding the NSCLC tumor microenvironment's immune landscape is crucial for treatment optimization.
Purpose of the Study:
- To analyze TIL profiles in NSCLC to identify immune subtypes.
- To correlate these subtypes with patient prognosis and molecular characteristics.
- To inform the development of personalized immunotherapies for NSCLC.
Main Methods:
- Analysis of TIL profiles from 281 fresh resected NSCLC tissues.
- Unsupervised clustering of 30 TIL types to define immune subtypes (cold, myeloid-dominant, CD8+ T cell-dominant).
- Integrated genomic and transcriptomic analyses (RNA-seq, WES, TCR repertoire, metabolomics).
Main Results:
- Three distinct NSCLC immune subtypes (cold, myeloid-dominant, CD8+ T cell-dominant) were identified, correlating with patient prognosis.
- The myeloid cell-dominant subtype exhibited worse patient outcomes.
- Inactivated immune signaling and activated glycolysis/K-ras pathways were observed in myeloid subtypes; specific genetic alterations (ALK, ROS1, TERT) were enriched in these subtypes.
Conclusions:
- TIL profiling provides a novel classification of NSCLC into three immune subtypes with prognostic significance.
- Subtype-specific molecular pathways and genomic alterations define distinct immune tumor microenvironments.
- These classifications are valuable for guiding personalized immune therapy strategies in NSCLC.
