HMOX1 expression influence the role of macrophage in EGFR-TKI resistance of lung adenocarcinoma

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the first-line therapy for lung adenocarcinoma (LUAD) patients having EGFR-sensitive mutations. Although it has significantly prolonged survival of patients, resistance to EGFR-TKI treatment can not be avoided. While many intrinsic factors related to resistance have been identified, little is known about the role of non-tumor cells, particularly macrophages in the tumor microenvironment (TME), in TKI resistance. In the current study, we performed scRNA-seq analysis on 7458 cells from 12 patients with EGFR-TKI sensitive or resistant tumors to investigate the differential tumor microenvironment in these tumors. We identified significant differences in the immune cell fractions that presented between EGFR-TKI sensitive and resistant tumors, with lymphocytes being the predominant immune cells in EGFR-TKI resistant tumors, while myeloid cells were more prominent in EGFR-TKI sensitive tumors. We identified HMOX1^hi macrophages, exhibiting an anti-inflammatory M2 polarization, are more abundant in EGFR-TKI resistant tumors than in EGFR-TKI sensitive tumors. We further revealed extensive communication between macrophages and CAM-related tumor cells through SPP1 and FN1 signaling. The findings suggested that manipulating HMOX1 expression in macrophages might change their function and modulate sensitivity of patients to EGFR-TKI.