Spatial transcriptomics reveals macrophage domestication by epithelial cells promotes immunotherapy resistance in small cell lung cancer
Yu Sun, Minghui Zhang, Yanbin Zhao, Yubo Yan, Lei Wang, Xuhui Liu, Songsong Xia, Bingbing Wang, Xiaoxin Zhang, Yan Wang
Abstract
Small cell lung cancer (SCLC) remains a lethal malignancy. Although immunochemotherapy regimens have improved patient survival rates, drug resistance still occurs in a significant subset of patients, highlighting the importance of elucidating the mechanisms within the tumor microenvironment. Here, we applied spatial single-cell transcriptomics to investigate the spatial characteristics of SCLC and their associations with immunochemotherapy resistance. By analyzing samples from 18 patients with extensive-stage SCLC, we identified two distinct epithelial cell subtypes: Epi-I and Epi-II. Epi-I exhibited high proliferative activity and was associated with treatment resistance and poor survival outcomes. In contrast, Epi-II showed more spatial contact with immune cells and was associated with treatment sensitivity. Further analysis uncovered a fascinating cellular transition paradigm, wherein Epi-I may be derived from Epi-II, with myeloid cells playing a facilitatory role in this transformation cascade. Specifically, within the spatial zone that was enriched with the Epi-II, epithelial cells may secrete MIF gene, which promoted the polarization of myeloid cells towards the M2 macrophages. The M2-polarized myeloid cells subsequently upregulated the expression of SPP1 that in turn triggered the activation of the PI3K-AKT signaling pathway in the adjacent epithelial cells, driving the conversion of Epi-II to Epi-I cells. Our findings revealed that the intricate crosstalk between epithelial and myeloid cells constitutes a pivotal resistance mechanism in SCLC, and targeting the SPP1/MIF pathway emerged as a promising strategy with the potential to enhance the treatment efficacy.