1807P - Spatial analyses revealed MMP7 as the biomarker of tumor boundary correlated with immune resistance in small cell lung cancer

Background

Small cell lung cancer (SCLC) presents as a highly aggressive malignancy characterized by early dissemination and a grim long-term prognosis. The tumor boundary is a niche composed of malignant cells in the outermost circle of solid tumors and non-malignant cells closely adjacent in spatial architecture. Cell composition of the tumor boundary profoundly affects tumor microenvironment remodeling, which remains unexplored in SCLC.

Methods

We conducted spatial transcriptome sequencing of 10X Genomics Visium on 21 formalin-fixed paraffin-embedding samples of SCLC patients. Two pathologists performed the pathological annotations. We manually delineated the tumor regions using the 10X-developed Loupe software and defined the tumor boundary as the nearest 2-spot width area near the outermost circle of the tumor area. Then we compared the differentially expressed genes (DEGs) and enriched pathways between tumor boundary and tumor cores.

Results

21 samples yielded more than 100,000 spots with 18025 genes in our study. The tumor boundary exhibited heightened proliferation and angiogenesis activities. Notably, we identified MMP7 as a potential biomarker for tumor boundary, which was also found to be highly expressed in tumor-invasive areas. Furthermore, transcription factors SOX10, ZEB1, and SNAI2 exhibited enhanced expression in tumor boundaries, which promoted tumor proliferation, migration, and epithelial-mesenchymal transition. High expression levels of MMP7 were associated with poorer survival outcomes. Importantly, our findings unveiled the ability of MMP7 to recruit immunosuppressive MRC1+ macrophages. Additionally, we observed elevated expression of numerous immune checkpoints, including HAVCR2 and TIGHT, in this microenvironment, indicating immune resistance.

Conclusions

This study revealed MMP7 as the biomarker of tumor boundary correlated with immune resistance in SCLC.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.