Cellular crosstalk of macrophages and therapeutic implications in non-small cell lung cancer revealed by integrative inference of single-cell transcriptomics

Lei Wu; Wenying Xia; Yiting Hua; Kun Fan; Yanfei Lu; Min Wang; Yuexinzi Jin; Wei Zhang; Shiyang Pan

doi:10.3389/fphar.2023.1295442

Cellular crosstalk of macrophages and therapeutic implications in non-small cell lung cancer revealed by integrative inference of single-cell transcriptomics

Front Pharmacol. 2023 Nov 15:14:1295442. doi: 10.3389/fphar.2023.1295442. eCollection 2023.

Authors

Lei Wu^#^{1

2}, Wenying Xia^#^{1

2}, Yiting Hua^#^{1

2}, Kun Fan^{1

2}, Yanfei Lu^{1

2}, Min Wang^{1

2}, Yuexinzi Jin^{1

2}, Wei Zhang^{1

2}, Shiyang Pan^{1

2}

Affiliations

¹ Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
² Branch of National Clinical Research Center for Laboratory Medicine, Nanjing, China.

^# Contributed equally.

Abstract

Introduction: Non-small cell lung cancer (NSCLC) exhibits heterogeneity with diverse immune cell infiltration patterns that can influence tumor cell behavior and immunotherapy. A comprehensive characterization of the tumor microenvironment can guide precision medicine. Methods: Here, we generated a single-cell atlas of 398170 cells from 52 NSCLC patients, and investigated the imprinted genes and cellular crosstalk for macrophages. Subsequently, we evaluated the effect of tumor cells on macrophages and verified the expression of marker genes using co-culture experiments, flow cytometry and RT-qPCR assays. Results: Remarkable macrophage adaptability to NSCLC environment was observed, which contributed to generating tumor-associated macrophages (TAMs). We identified 5 distinct functional TAM subtypes, of which the majority were SELENOP-positive macrophages, with high levels of SLC40A1 and CCL13. The TAMs were also involved in mediating CD8⁺ T cell activity and form intercellular interaction with cancer cells, as indicated by receptor-ligand binding. Indirect coculture of tumor cells SPC-A1 and THP-1 monocytes, produced M2-like TAMs that highly expressed several markers of SELENOP-positive macrophages. The abundance of this type TAMs seemed to be associated with poorer overall survival rates [hazard ratio (HR) = 1.34, 95% confidence interval (CI) = 0.98-1.83, p = 0.068] based on deconvolution of TCGA-LUAD dataset. Discussion: In summary, we provided a high-resolution molecular resource of TAMs, and displayed the acquired properties in the tumor microenvironment. Dynamic crosstalk between TAMs and tumor cells via multiple ligand-receptor pairs were revealed, emphasizing its role in sustaining the pro-tumoral microenvironment and its implications for cancer therapy.

Keywords: NSCLC; cellular crosstalk; scRNA-seq; therapeutic implications; tumor-associated macrophages.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was funded by the National Natural Science Foundation of China (Grant No. 82272401).