A Cross-Species Nerve- and Airway-Associated Macrophage Program that Drives Lung Tumor Progression and Immunotherapy Resistance 2301331

Abstract Introduction Nerve- and airway-associated interstitial macrophages (NAMs) are a distinct subset of lung-resident macrophages with key immunoregulatory roles during respiratory viral infections. Previous research has highlighted their indispensable function in suppressing inflammation and promoting tissue homeostasis, establishing them as critical mediators of disease tolerance during lung infection. However, their role in the context of lung cancer remains largely unexplored. Methods To investigate the role of NAMs in lung tumor progression, we employed diphtheria toxin receptor (DTR) and gene-conditional knockout transgenic mouse models in combination with confocal microscopy and transcriptomic analyses of both murine and human lung tumor samples. Results Selective depletion of NAMs using transgenic NAM-DTR mice revealed a significant reduction in tumor burden across multiple lung tumor models. Furthermore, NAM depletion synergized with anti-PD-1 therapy to amplify CD8+ T cell responses and markedly enhance therapeutic efficacy. Extending these findings to patients, single-nucleus RNA sequencing of a lung cancer patient cohort demonstrated that higher NAM abundance in tumor biopsies was associated with both shorter overall survival and reduced progression-free survival. Consistent with this, transcriptomic analysis of a single-cell RNA sequencing dataset from an immunotherapy-treated cohort revealed that low-responder patients harbored a pronounced enrichment of NAMs compared to high-responders. Strikingly, within the low-responder group, NAM frequency exhibited a strong negative correlation with PD-1+TCF1+CD8+ T cells, the critical T cell reservoir required for durable responses to checkpoint blockade therapy. Conclusion Collectively, these findings identify NAMs as a previously underappreciated myeloid population that actively orchestrates an immunosuppressive tumor microenvironment and underscore their potential as a novel, targetable barrier to effective immunotherapy in lung cancer. Funding Source n/a Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)