CSF1R-dependent CD169-positive macrophages locally constrain melanoma growth in the skin.
Keith Yuki Honda, Duchini Emily, Lin Xufeng, Kyaw Wunna, Weninger Felix G P, Dhenni Rama, Telfser Aiden Josiah, Grootveld Abigail K, Barkauskas Deborah, Fontaine-Titley Angela, Tikoo Shweta, Jain Rohit, Weninger Wolfgang, Frew John W, Deenick Elissa K, Brink Robert, Martin Linda K, Chtanova Tatyana, Goldstein Leonard D, Scolyer Richard A, Long Georgina V, Palendira Umaimainthan, Phan Tri Giang
Abstract
Macrophages in the skin reside in multiple distinct layers and perform various functions. Here, we show that CD169+ macrophages reside in the hypodermis and comprise the major skin myeloid cell population in the steady state. In a syngeneic melanoma model, CD169+ macrophages encapsulate growing melanomas and directly suppress their growth. CSF1R blockade depleted CD169+ macrophages in tumors and resulted in unrestrained growth. This local containment of tumor growth in the skin was independent of CD169+ subcapsular sinus macrophages in the tumor-draining lymph node and did not require B or T cells. Intravital imaging revealed engulfment and ingestion of live tumor cells by CD169+ macrophages. This phagocytosis did not require the phosphatidylserine receptor MERTK. CD169+ macrophages are also enriched in the hypodermis in skin biopsies from healthy human skin and melanoma. These data identify tissue-resident CD169+ macrophages as a potential cellular target to achieve innate immune containment and reinforce adaptive immune control of tumors.
Key Findings
- CD169+ macrophages reside in the hypodermis and are the major skin myeloid cell population in steady state.
- CD169+ macrophages encapsulate and directly suppress melanoma growth in a syngeneic melanoma model.
- CSF1R blockade depletes CD169+ macrophages leading to unrestrained tumor growth, independent of adaptive immune cells.
- CD169+ macrophages phagocytose live tumor cells without requiring the MERTK receptor.
- Similar CD169+ macrophages are enriched in human healthy skin and melanoma biopsies.
Clinical Significance
Targeting tissue-resident CD169+ macrophages may enhance innate immune containment of melanoma and support adaptive immune tumor control, representing a potential therapeutic strategy in cancer immunotherapy.
Citation
Keith Yuki Honda, Duchini Emily, Lin Xufenget al.. CSF1R-dependent CD169-positive macrophages locally constrain melanoma growth in the skin. The Journal of experimental medicine. 2026-Jul-06.