165P - Immunosuppressive F13A1+ Mo/M_ in the tumor microenvironment as a hallmark for multiple primary lung cancers

Background

The increasing number of patients with multiple primary lung cancers (MPLCs) endows a rising challenge for clinical management. The tumor microenvironment (TME) has a critical role in MPLCs but its contribution to cancer onset remains unclear. Further explorations of TME via single cell transcriptomics would allow for discovery of diagnostic biomarkers and potential therapeutic targets for MPLCs, differing from solitary primary lung cancers (SPLCs).

Methods

We profiled 13 tumors and paired paracancerous samples from 5 MPLC and 3 SPLC patients using single-cell RNA sequencing (scRNA-seq). Seurat was used for dimensional reduction, cluster identification and cell type annotation. Myeloid clusters were analyzed for their marker gene expression and tissue distribution. Cell-cell communication was examined using CellChat. Results were validated in scRNA-seq datasets from independent external cohorts (GSE200972 and E-MTAB-6149), including 25 samples from 4 MPLCs and 3 SPLCs.

Results

We classified 79,944 Monocytes/Macrophages (Mo/Mϕ) into 5 clusters based on the expression of FABP4, F13A1, FCN1, LYVE1 and MKI67. Of note, the F13A1+ Mo/Mϕ subset is preferentially enriched in MPLC tumors rather than normal tissues or SPLC tumors. They display a transcriptional profile resembling M2-like Mϕs and SPP1-expressing Mϕs that are pro-tumor and associated with poor prognosis. They also express high levels of anti-inflammatory markers and low levels of pro-inflammatory genes. CellChat analysis revealed a strong interaction between F13A1+ Mo/Mϕ and NK/T cells in MPLCs, but not SPLCs, via SPP1:CD44 and HLA-E:NKG2A axes, both of which have a negative impact on anti-tumor immunity. These findings were further validated in independent datasets.

Conclusions

We identified a previously undescribed F13A1+ Mo/Mϕ subpopulation preferentially enriched in MPLCs. Our data suggest that they could serve as a diagnostic biomarker to distinguish MPLCs from normal tissues and SPLCs. Crosstalk between F13A1+ Mo/Mϕ and immune cells through specific ligand-receptor interactions may contribute to immune suppression during cancer development, which could be a specific druggable target for MPLCs.

Legal entity responsible for the study

Cancer Hospital Chinese Academy of Medical Sciences, Shenzhen Center.

Funding

National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen+SZ2020ZD011; Medical Scientific Research Foundation of Guangdong Province, China; Sanming Project of Medicine in Shenzhen (No. SZSM201612097) and Shenzhen Key Medical Discipline Construction fund (No. SZXK075).

Disclosure

All authors have declared no conflicts of interest.