Targeting CD206+ macrophages disrupts the establishment of a key antitumor immune axis

Arja Ray; Kenneth H Hu; Kelly Kersten; Tristan Courau; Nicholas F Kuhn; Itzia Zaleta-Linares; Bushra Samad; Alexis J Combes; Matthew F Krummel

doi:10.1084/jem.20240957

Targeting CD206+ macrophages disrupts the establishment of a key antitumor immune axis

J Exp Med. 2025 Jan 6;222(1):e20240957. doi: 10.1084/jem.20240957. Epub 2024 Nov 27.

Authors

Arja Ray^{1

2}, Kenneth H Hu^{1

2}, Kelly Kersten^{1

2}, Tristan Courau^{1

2}, Nicholas F Kuhn^{1

2}, Itzia Zaleta-Linares^{1

2}, Bushra Samad^{2

3}, Alexis J Combes^{1

2

3

4}, Matthew F Krummel^{1

2

3}

Affiliations

¹ Department of Pathology, University of California, San Francisco, CA, USA.
² ImmunoX Initiative, University of California, San Francisco, CA, USA.
³ UCSF CoLabs, University of California, San Francisco, CA, USA.
⁴ Department of Medicine, University of California, San Francisco, CA, USA.

PMID: 39601781
PMCID: PMC11602655 (available on 2025-05-27)
DOI: 10.1084/jem.20240957

Abstract

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.

MeSH terms

Animals
CD8-Positive T-Lymphocytes* / immunology
Chemokine CXCL9 / genetics
Chemokine CXCL9 / metabolism
Dendritic Cells / immunology
Dendritic Cells / metabolism
Gene Knock-In Techniques
Humans
Killer Cells, Natural* / immunology
Lectins, C-Type* / genetics
Lectins, C-Type* / metabolism
Macrophages* / immunology
Macrophages* / metabolism
Mannose Receptor
Mannose-Binding Lectins / metabolism
Membrane Glycoproteins / genetics
Membrane Glycoproteins / metabolism
Mice
Mice, Inbred C57BL
Monocytes / immunology
Monocytes / metabolism
Neoplasms / genetics
Neoplasms / immunology
Receptors, CXCR3 / genetics
Receptors, CXCR3 / metabolism
Receptors, Cell Surface* / genetics
Receptors, Cell Surface* / metabolism
Receptors, Chemokine
Receptors, Immunologic / genetics
Receptors, Immunologic / metabolism
Tumor-Associated Macrophages / immunology
Tumor-Associated Macrophages / metabolism

Substances

Lectins, C-Type
Receptors, Cell Surface
Mannose Receptor
Mannose-Binding Lectins
Receptors, CXCR3
Chemokine CXCL9
Cxcr3 protein, mouse
MRC1 protein, human
Membrane Glycoproteins
Receptors, Immunologic
XC chemokine receptor 1, mouse
Receptors, Chemokine

Abstract

MeSH terms

Substances

Grants and funding