Multiomics elucidation of surrounding AT2 cells impeding tertiary lymphoid structures function in neoadjuvant chemoimmunotherapy response of multiple primary lung cancers

The inconsistent immunotherapy response among lesions in patients with multiple primary lung cancer (MPLC) remains poorly understood, presenting a significant challenge for effective treatment. In this study, we conducted a comprehensive multiomics analysis of all lesions from a patient with MPLC who exhibited varied responses to neoadjuvant chemoimmunotherapy. Further verification was conducted through external single-cell data and multiplex immunohistochemistry of three cases of MPLC.Notably, tertiary lymphoid structures (TLSs) were observed across all nodules, regardless of response, suggesting possible TLS impairment in non-responsive nodules. Cell neighborhood (CN) analysis revealed that type II alveolar epithelial cell (AT2) cell–positive CNs were prevalent in non-responsive nodules, while AT2-negative CNs appeared in responsive nodules, strongly associating AT2 cell presence with a reduced therapeutic response. Spatial colocalization analysis further showed that AT2 cells surrounding TLSs upregulated immunosuppressive markers on B cells within TLSs. The mechanism of this suppressive effect was further unveiled that macrophage migration inhibitory factor (MIF), secreted by AT2 cells, binds to sialic acid acetylesterase (SIAE) receptors on B cells by single-cell RNA sequencing analysis, which were validated in four additional non-responsive nodules from three other patients with MPLC. Multiomics analysis revealed AT2 cells exert immunosuppressive effects by inhibiting B cells within TLS through MIF-SIAE signaling axis in patients with MPLC. These findings offered new perspectives for tailored immunotherapy for patients with MPLC.