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.
Author Info: (1) Department of Microbiology and Immunology, Dartmouth Geisel School of Medicine, Hanover, NH, USA. (2) Department of Microbiology and Immunology, Dartmouth Geisel School of Medi
Author Info: (1) Department of Microbiology and Immunology, Dartmouth Geisel School of Medicine, Hanover, NH, USA. (2) Department of Microbiology and Immunology, Dartmouth Geisel School of Medicine, Hanover, NH, USA. (3) Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA. (4) Department of Microbiology and Immunology, Dartmouth Geisel School of Medicine, Hanover, NH, USA. (5) Department of Microbiology and Immunology, Dartmouth Geisel School of Medicine, Hanover, NH, USA. (6) Department of Microbiology and Immunology, Dartmouth Geisel School of Medicine, Hanover, NH, USA. (7) Dartmouth Cancer Center, Dartmouth Geisel School of Medicine, Hanover, NH, USA. (8) Dartmouth Cancer Center, Dartmouth Geisel School of Medicine, Hanover, NH, USA. (9) Department of Microbiology and Immunology, Dartmouth Geisel School of Medicine, Hanover, NH, USA. claudia.jakubzick@dartmouth.edu.
