In Vivo Labeling Resolves Distinct Temporal, Spatial, and Functional Properties of Tumor Macrophages and Identifies...

Area of Science:

• Immunology
• Cancer Biology
• Cellular Biology

Background:

• Tumor-associated macrophages (TAMs) are prevalent in cancers, influencing patient outcomes and treatment efficacy.
• Understanding TAM heterogeneity and dynamics is crucial for developing effective cancer therapies.

Purpose of the Study:

• To differentiate and characterize newly entering monocyte-derived TAMs (mdTAMs) from resident-like TAMs.
• To investigate the functional divergence and temporal changes of mdTAM subsets.
• To elucidate the effects of anti-PD-L1 therapy on TAMs and the tumor immune microenvironment.

Main Methods:

• Utilized a photoconvertible mouse model to track monocyte-derived TAMs (mdTAMs).
• Distinguished TAM subsets based on MHC class II expression and analyzed their functional properties.
• Assessed the impact of anti-PD-L1 treatment on TAM differentiation and immune cell interactions.

Main Results:

• Newly entering mdTAMs were enriched in the tumor core and divided into MHC-II+ and MHC-II- subsets with distinct functions.
• Both mdTAM subsets exhibited increased PD-L1 expression and reduced inflammatory profiles with longer tumor residence.
• Anti-PD-L1 treatment promoted MHC-II+ mdTAM differentiation, reduced tumor-associated inflammation, and enhanced T cell interactions.

Conclusions:

• TAM populations are heterogeneous, with distinct subsets arising from circulating monocytes.
• TAM functional properties change over time within the tumor microenvironment.
• Targeting PD-L1 modulates TAM differentiation and fosters an anti-tumor immune response through specific feedback loops.