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Updated: Mar 6, 2026
Predictive Immune Modeling of Solid Tumors
Published on: February 25, 2020
Single-cell profiling of tumor lineage plasticity and the immune microenvironment in transformed small cell lung
Jie Huang1,2, Zhenhua Zhang3, Guodi Cai3
1Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, 510080, China.
Background:
The transformation of non-small cell lung cancer (NSCLC) into small cell lung cancer (SCLC) is a recognized treatment resistance mechanism, most often arising from EGFR-mutant lung adenocarcinoma (LUAD). However, the underlying mechanisms of transformation remain poorly understood.
Methods:
Single-cell RNA sequencing was employed to analyze the tumor cell heterogeneity and to map the intratumoral immune cell landscape of 73,195 cells from five LUAD, three transformed small cell lung cancer (T-SCLC) and four SCLC patients. Multiplex immunofluorescence (mIF) staining and in vitro studies were further conducted to validate the stem-like feature of a malignant cell cluster and the enrichment and the function of interferon-stimulated gene-positive (ISG+) lymphocytes in transformation.
Results:
Although increased intratumoral heterogeneity was observed upon SCLC transformation, a stem-like malignant cell subpopulation was identified to recur across subtypes and groups as the pioneering force of lineage plasticity for SCLC transformation. Further mIF staining and transcription factor analysis validated the stem-like feature. Additionally, tumor immune microenvironment (TIME) analysis revealed that ISG+ T cells and B cells were enriched in T-SCLC. Further cell co-culture analyses disclosed that ISG+ lymphocytes promoted neuroendocrine differentiation in LUAD cells via type I interferons (IFN-Is). Deciphering cell-cell interactions revealed that the stem-like malignant cells might activate and attract ISG+ T cells. Finally, we developed an ISG-associated gene signature that significantly correlates with poor prognosis in LUAD.
Conclusion:
Our findings provide a comprehensive understanding of the lineage plasticity and the immune landscape in T-SCLC, highlighting the crucial role of the stem-like cell cluster and ISG+ lymphocytes in LUAD-to-SCLC transformation.
Insights
A stem-like cell cluster drives non-small cell lung cancer (NSCLC) transformation into small cell lung cancer (SCLC). Interferon-stimulated gene-positive (ISG+) lymphocytes promote this transformation, impacting treatment resistance.
Area of Science:
- Oncology
- Cancer Biology
- Immunology
Background:
- Transformation of EGFR-mutant lung adenocarcinoma (LUAD) to small cell lung cancer (SCLC) is a treatment resistance mechanism.
- The precise mechanisms driving LUAD to SCLC transformation are not well understood.
Purpose of the Study:
- To investigate the cellular and immune landscape during LUAD to SCLC transformation.
- To identify key drivers of lineage plasticity and immune cell roles in this process.
Main Methods:
- Single-cell RNA sequencing of 73,195 cells from LUAD, transformed SCLC (T-SCLC), and SCLC patients.
- Multiplex immunofluorescence (mIF) and in vitro studies to validate findings.
- Analysis of tumor immune microenvironment (TIME) and cell-cell interactions.
Main Results:
- A recurrent stem-like malignant cell subpopulation identified as a driver of SCLC transformation.
- Enrichment of interferon-stimulated gene-positive (ISG+) T cells and B cells in T-SCLC.
- ISG+ lymphocytes promote neuroendocrine differentiation in LUAD cells via type I interferons (IFN-Is).
- Stem-like cells may activate and attract ISG+ T cells.
- An ISG-associated gene signature correlates with poor LUAD prognosis.
Conclusions:
- Stem-like cells and ISG+ lymphocytes are crucial in LUAD-to-SCLC transformation.
- Provides comprehensive insights into lineage plasticity and immune landscape in T-SCLC.
