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979 Phagocytosis increases an oxidative metabolic and immune suppressive signature in tumor macrophages
  1. Michael Gonzalez1,
  2. Daniel Lu1,
  3. Chen Hao Lo1,
  4. Maryam Yousefi2,
  5. Ashley Kroll1,
  6. Monte Winslow2 and
  7. Kristin Tarbell1
  1. 1Amgen Research, South San Francisco, CA, USA
  2. 2Stanford University School of Medicine, Stanford, CA, USA
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


Background Tumor-associated macrophage (TAMs) are one of the most abundant immune cell types in tumors, and their numbers often inversely correlate with clinical outcome. Phagocytosis is a key macrophage function, but how phagocytosis shapes TAM phenotypes and heterogeneity in solid tumors remains unclear.

Methods We have utilized both syngeneic and novel autochthonous lung tumor models in which specifically neoplastic cells express the fluorophore tdTomato (tdTom) to identify TAMs that have phagocytosed neoplastic cells in vivo. Gene expression was assessed by scRNAseq, and protein expression by flow cytometry and immunofluorescence. Functional metabolic assays included extracellular flux analysis.

Results Phagocytic tdTompos TAMs upregulated antigen presentation and anti-inflammatory proteins, but downregulated classic proinflammatory effectors compared to tdTomneg TAMs. Single-cell transcriptomic profiling identified TAM subset-specific and common gene expression changes associated with phagocytosis. We uncover a phagocytic signature that is predominated by oxidative phosphorylation (OXPHOS), ribosomal, and metabolic genes, and this signature correlates with worse clinical outcome in human lung cancer. Expression of OXPHOS proteins, mitochondrial content, and functional utilization of OXPHOS were increased in tdTompos TAMs. tdTompos tumor dendritic cells also display similar metabolic changes. Tumor phagocytosis-induced metabolic and inflammation-modulatory changes were confirmed in vitro using bone marrow macrophage and tumor cell co-culture assays.

Conclusions Our identification of phagocytic TAMs as a distinct myeloid cell state links phagocytosis of neoplastic cells in vivo with changes in intracellular metabolism, specifically increased OXPHOS, and with tumor-promoting phenotypes.

Ethics Approval All animal experimental protocols performed at Amgen were approved by the IACUC of Amgen and were conducted in accordance with the guidelines set by the Association for Assessment and Accreditation of Laboratory Animal Care. The Stanford Institute of Medicine Animal Care and Use Committee approved all animal studies and procedures performed at Stanford University.

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