<i>In Vivo</i> Labeling Resolves Distinct Temporal, Spatial, and Functional Properties of Tumor Macrophages and Identifies Subset-Specific Effects of PD-L1 Blockade

Tumor-associated macrophages (TAM) are a universal feature of cancers but variably influence outcomes and treatment responses. In this study, we used a photoconvertible mouse to distinguish newly entering, monocyte-derived TAMs (mdTAM) that were enriched at the tumor core from resident-like TAMs that localized with fibroblasts at the tumor-normal interface. The mdTAM pool was highly dynamic and continually replenished by circulating monocytes. Upon tumor entry, these monocytes differentiated down two divergent fate trajectories distinguished by the expression of MHC class II. MHC-II+ mdTAMs were functionally distinct from MHC-II- mdTAMs, demonstrating increased capacity for endocytosis and Fc-gamma receptor-mediated phagocytosis, as well as proinflammatory cytokine production. Both mdTAM subsets showed reduced expression of inflammatory transcripts and increased expression of PD-L1 with increasing tumor dwell time. Treatment with anti-PD-L1 skewed mdTAM differentiation toward the MHC-II+ fate and attenuated the anti-inflammatory effects of the tumor environment. Anti-PD-L1 enhanced mdTAM-CD4+ T cell interactions, establishing an IFNγ-CXCL9/10-dependent positive feedback loop. Altogether, these data resolve distinct temporal, spatial, and functional properties of TAMs and provide evidence of subset-specific effects of PD-L1 blockade.

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Publication Details

Journal
Cancer Immunology Research
Published
2025-06-16
DOI
https://doi.org/10.1158/2326-6066.cir-24-1233
Citations
2
Primary Topic
Immune cells in cancer
Type
article
Field-Weighted Citation Impact
1.59
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article

In Vivo Labeling Resolves Distinct Temporal, Spatial, and Functional Properties of Tumor Macrophages and Identifies Subset-Specific Effects of PD-L1 Blockade

Zewen Kelvin Tuong, Nathan Richoz, David R. Withers, Bethany C. Kennedy et al.
2 citations
Cancer Immunology Research
Immune cells in cancer
1.59
article

In Vivo Labeling Resolves Distinct Temporal, Spatial, and Functional Properties of Tumor Macrophages and Identifies Subset-Specific Effects of PD-L1 Blockade

Zewen Kelvin Tuong, Nathan Richoz, David R. Withers, Bethany C. Kennedy, Colin Y.C. Lee, Isaac Dean, Timotheus Y.F. Halim, Kathryn Gilroy, Owen J. Sansom, Gianluca Carlesso, Simon J. Dovedi, Scott A. Hammond, Lisa A. Vettore, Menna Ruth Clatworthy, Youhani Samarakoon, Zhi Li, Tetsuo Hasegawa
article en
2 citations

Abstract

Tumor-associated macrophages (TAM) are a universal feature of cancers but variably influence outcomes and treatment responses. In this study, we used a photoconvertible mouse to distinguish newly entering, monocyte-derived TAMs (mdTAM) that were enriched at the tumor core from resident-like TAMs that localized with fibroblasts at the tumor-normal interface. The mdTAM pool was highly dynamic and continually replenished by circulating monocytes. Upon tumor entry, these monocytes differentiated down two divergent fate trajectories distinguished by the expression of MHC class II. MHC-II+ mdTAMs were functionally distinct from MHC-II- mdTAMs, demonstrating increased capacity for endocytosis and Fc-gamma receptor-mediated phagocytosis, as well as proinflammatory cytokine production. Both mdTAM subsets showed reduced expression of inflammatory transcripts and increased expression of PD-L1 with increasing tumor dwell time. Treatment with anti-PD-L1 skewed mdTAM differentiation toward the MHC-II+ fate and attenuated the anti-inflammatory effects of the tumor environment. Anti-PD-L1 enhanced mdTAM-CD4+ T cell interactions, establishing an IFNγ-CXCL9/10-dependent positive feedback loop. Altogether, these data resolve distinct temporal, spatial, and functional properties of TAMs and provide evidence of subset-specific effects of PD-L1 blockade.

Cancer Immunology ResearchVol. 13(9)
AstraZeneca (United Kingdom) (GB), Institute of Cancer Research (GB), The University of Queensland (AU), MRC Laboratory of Molecular Biology (GB), University of Cambridge (GB), Wellcome Sanger Institute (GB), University of Oxford (GB), Cancer Research UK Cambridge Center (GB), AstraZeneca (Netherlands) (NL), AstraZeneca (Singapore) (SG), Oxford Centre for Diabetes, Endocrinology and Metabolism (GB), Cancer Research UK Scotland Institute (GB), AstraZeneca (United States) (US), Foster Care Associates Scotland (GB), University of Birmingham (GB), Medical Research Council (GB)
Good health and well-being
Openalex Percentile: Top 16%
Immune cells in cancer
1.59
DOIOpen Access PDFOpenAlex
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