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Multi-Omics reveals SPP1 + malignant and CXCR4+ TAM crosstalk predicts immunotherapy response in lung adenocarcinoma
Bei Li Wang1, Juan Wen Lian1, Jia Ling Xu1
1Xi 'an Chest Hospital, Xi 'an, 710010, Shaanxi, China.
Background:
Lung adenocarcinoma (LUAD), a common lung cancer subtype, is significantly influenced by the immune microenvironment. Immune checkpoint inhibitors have shown limited efficacy in Lung adenocarcinoma due to the immunosuppressive tumor microenvironment (TME). Identifying predictive biomarkers for immunotherapy response remains an urgent clinical need.
Methods:
Multi-Omics data of LUAD were analyzed to investigate the immune microenvironment in LUAD. Single cell RNA-seq was used for exploring the intercellular communication mechanisms in TME. Spatial transcriptomic analysis confirmed the spatial co-localization of SPP1+ Malignant and CXCR4+ TAM, while in vitro experiments validated the functions of biomarker.
Results:
This study delineated the cellular heterogeneity and dynamic shifts within the LUAD tumor microenvironment, resolving the malignant transformation trajectory. Crucially, we identified SPP1⁺ malignant and CXCR4⁺ TAM crosstalk as a driver of exhaustion of CD8T, which induced poor immunotherapy response. Moreover, this study indicated that the immune escape potential of patients in high infiltration of SPP1+ malignant and CXCR4+ TAM increased, and the efficacy of immune checkpoint suppressive therapy might be poorer. Spatial transcriptomics confirmed co-localization of SPP1+ Malignant and CXCR4+ TAM, while in vitro experiments demonstrated that CXCR4 plays an important role in the functions of LUAD cells.
Conclusions:
This study uncovers the SPP1⁺ malignant and CXCR4⁺ TAM crosstalk as a novel TME-driven resistance mechanism and provides a potential biomarker for stratifying LUAD patients likely to benefit from immunotherapy.
Insights
Researchers identified SPP1+ malignant cells and CXCR4+ TAM crosstalk as a key factor in poor immunotherapy response in lung adenocarcinoma (LUAD). This finding offers a potential biomarker for predicting treatment success in LUAD patients.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Lung adenocarcinoma (LUAD) is a major lung cancer subtype influenced by its immune microenvironment.
- The immunosuppressive tumor microenvironment (TME) limits the efficacy of immune checkpoint inhibitors in LUAD.
- There is a critical need for biomarkers to predict immunotherapy response in LUAD.
Purpose of the Study:
- To investigate the immune microenvironment in LUAD using multi-omics data.
- To explore intercellular communication mechanisms within the LUAD TME.
- To identify potential biomarkers for immunotherapy response in LUAD.
Main Methods:
- Analysis of multi-omics data from LUAD.
- Single-cell RNA sequencing to study intercellular communication in the TME.
- Spatial transcriptomic analysis to confirm co-localization of specific cell types.
- In vitro experiments to validate biomarker functions.
Main Results:
- Identified crosstalk between SPP1+ malignant cells and CXCR4+ tumor-associated macrophages (TAMs) as a driver of CD8+ T cell exhaustion.
- This crosstalk was associated with poor immunotherapy response and increased immune escape potential in LUAD patients.
- Spatial transcriptomics confirmed the co-localization of SPP1+ malignant cells and CXCR4+ TAMs, with in vitro studies highlighting CXCR4's role in LUAD cell function.
Conclusions:
- SPP1+ malignant and CXCR4+ TAM crosstalk represents a novel TME-driven mechanism of resistance to immunotherapy in LUAD.
- This crosstalk serves as a potential biomarker for stratifying LUAD patients who may benefit from immunotherapy.
- Understanding this interaction is crucial for improving therapeutic strategies in LUAD.
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