CD206 is a common marker of a putative immunosuppressive “M2” state in tumor-associated macrophages (TAMs). We made a novel conditional CD206 (Mrc1) knock-in mouse to specifically visualize and/or deplete CD206+ TAMs. Early depletion of CD206+ macrophages and monocytes (Mono/Macs) led to the indirect loss of conventional type I dendritic cells (cDC1), CD8 T cells, and NK cells in tumors. CD206+ TAMs robustly expressed CXCL9, contrasting with stress-responsive Spp1-expressing TAMs and immature monocytes, which became prominent with early depletion. CD206+ TAMs differentially attracted activated CD8 T cells, and the NK and CD8 T cells in CD206-depleted tumors were deficient in Cxcr3 and cDC1-supportive Xcl1 and Flt3l expressions. Disrupting this key antitumor axis decreased tumor control by antigen-specific T cells in mice. In human cancers, a CD206Replete, but not a CD206Depleted Mono/Mac gene signature correlated robustly with CD8 T cell, cDC1, and NK signatures and was associated with better survival. These findings negate the unqualified classification of CD206+ “M2-like” macrophages as immunosuppressive.
Targeting CD206+ macrophages disrupts the establishment of a key antitumor immune axis
Disclosures: A.J. Combes reported grants from Eli Lily, grants from Genentech, other from Foundery Innovations, and other from Survey Genomics outside the submitted work. No other disclosures were reported.
K.H. Hu’s current affiliation is Department of Immunology, The University of Texas MD Anderson Cancer Center and James P Allison Institute, Houston, TX, USA.
K. Kersten’s current affiliation is Cancer Metabolism and Microenvironment Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
- Award Id(s): R01CA197363,R37AI052116
- Award Id(s): CRI2940,CRI4546
Arja Ray, Kenneth H. Hu, Kelly Kersten, Tristan Courau, Nicholas F. Kuhn, Itzia Zaleta-Linares, Bushra Samad, Alexis J. Combes, Matthew F. Krummel; Targeting CD206+ macrophages disrupts the establishment of a key antitumor immune axis. J Exp Med 6 January 2025; 222 (1): e20240957. doi: https://doi.org/10.1084/jem.20240957
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