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Sci Transl Med. 2019 Feb 13;11(479). pii: eaat1500. doi: 10.1126/scitranslmed.aat1500.

Human tumor-associated monocytes/macrophages and their regulation of T cell responses in early-stage lung cancer.

Author information

1
Division of Thoracic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, PA 19104, USA.
2
Division of Pulmonary, Allergy, and Critical Care, University of Pennsylvania, Philadelphia, PA 19104, USA.
3
Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, PA 19104, USA.
4
Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
5
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
6
Division of Transplantation Immunology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
7
Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
8
Division of Thoracic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, PA 19104, USA. evgeniy.eruslanov@uphs.upenn.edu.

Abstract

Data from mouse tumor models suggest that tumor-associated monocyte/macrophage lineage cells (MMLCs) dampen antitumor immune responses. However, given the fundamental differences between mice and humans in tumor evolution, genetic heterogeneity, and immunity, the function of MMLCs might be different in human tumors, especially during early stages of disease. Here, we studied MMLCs in early-stage human lung tumors and found that they consist of a mixture of classical tissue monocytes and tumor-associated macrophages (TAMs). The TAMs coexpressed M1/M2 markers, as well as T cell coinhibitory and costimulatory receptors. Functionally, TAMs did not primarily suppress tumor-specific effector T cell responses, whereas tumor monocytes tended to be more T cell inhibitory. TAMs expressing relevant MHC class I/tumor peptide complexes were able to activate cognate effector T cells. Mechanistically, programmed death-ligand 1 (PD-L1) expressed on bystander TAMs, as opposed to PD-L1 expressed on tumor cells, did not inhibit interactions between tumor-specific T cells and tumor targets. TAM-derived PD-L1 exerted a regulatory role only during the interaction of TAMs presenting relevant peptides with cognate effector T cells and thus may limit excessive activation of T cells and protect TAMs from killing by these T cells. These results suggest that the function of TAMs as primarily immunosuppressive cells might not fully apply to early-stage human lung cancer and might explain why some patients with strong PD-L1 positivity fail to respond to PD-L1 therapy.

Comment in

PMID:
30760579
PMCID:
PMC6800123
DOI:
10.1126/scitranslmed.aat1500
[Indexed for MEDLINE]
Free PMC Article

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