Ghosh et al. demonstrated that tissue-resident interstitial macrophages (IMs) and recruited macrophages (recMacs) showed distinct gene expression profiles in B16F10 lung metastases and KPAR1.3 lung tumor models. CD206hi IM subsets (Cxcl13+, Cxcl9+, Cxcl10+) were localized in bronchovascular regions and promoted TLS formation and lymphocyte recruitment, whereas CD206lo Ccl2+ IMs recruited Ly6c2+Fn1+Vcan+ recMacs with tumor-promoting transcriptional programs. In tdLNs, Ly6C+ monocyte-derived dendritic cells acted as immunosuppressive APCs during neoantigen vaccination, and CCR5 blockade limited their migration, enhancing antitumor immunity.
Contributed by Shishir Pant
ABSTRACT: Macrophages are among the most abundant immune cells in solid tumors, yet how macrophage lineage and spatial organization shape antitumor immunity remains unclear. Here we uncovered a division of labor between tissue-resident CD206(hi) and CD206(lo) interstitial macrophage (IM) subsets and Ly6c2(+)Fn1(+)Vcan(+) recruited macrophages (recMacs) in lung cancer. Using single-cell and spatial transcriptomics, we identified chemokine-expressing IM subsets with opposing functions. Cxcl13(+)CD206(hi) IMs, Cxcl9(+)CD206(hi) IMs and Cxcl10(+)CD206(hi) IMs positioned along bronchovascular regions drove tertiary lymphoid structure formation, lymphocyte recruitment and tumor control, whereas Ccl2(+) IMs, localized within tumor regions, recruited protumorigenic Ly6c2(+)Fn1(+)Vcan(+) recMacs. In addition, Ly6C(+)CD11b(+) monocyte-derived dendritic cells (moDCs) functioned as immunosuppressive antigen-presenting cells in tumor-draining lymph nodes. During neoantigen vaccination, CCR5 blockade with maraviroc selectively inhibited antigen-bearing moDC migration, enhancing dendritic cell-mediated antitumor immunity. These findings showed how macrophage lineage and spatial compartmentalization govern tumor immunity and identified strategies to preserve protective IM functions, while disrupting macrophage-driven immunosuppression.
