Macrophages impede CD8 T cells from reaching tumor cells and limit the efficacy of anti-PD-1 treatment

Proc Natl Acad Sci U S A. 2018 Apr 24;115(17):E4041-E4050. doi: 10.1073/pnas.1720948115. Epub 2018 Apr 9.


In a large proportion of cancer patients, CD8 T cells are excluded from the vicinity of cancer cells. The inability of CD8 T cells to reach tumor cells is considered an important mechanism of resistance to cancer immunotherapy. We show that, in human lung squamous-cell carcinomas, exclusion of CD8 T cells from tumor islets is correlated with a poor clinical outcome and with a low lymphocyte motility, as assessed by dynamic imaging on fresh tumor slices. In the tumor stroma, macrophages mediate lymphocyte trapping by forming long-lasting interactions with CD8 T cells. Using a mouse tumor model with well-defined stromal and tumor cell areas, macrophages were depleted with PLX3397, an inhibitor of colony-stimulating factor-1 receptor (CSF-1R). Our results reveal that a CSF-1R blockade enhances CD8 T cell migration and infiltration into tumor islets. Although this treatment alone has minor effects on tumor growth, its combination with anti-PD-1 therapy further increases the accumulation of CD8 T cells in close contact with malignant cells and delays tumor progression. These data suggest that the reduction of macrophage-mediated T cell exclusion increases tumor surveillance by CD8 T cells and renders tumors more responsive to anti-PD-1 treatment.

Keywords: T cells; cancer; immunotherapy; macrophages; migration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopyridines / pharmacology
  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / pathology
  • Carcinoma, Squamous Cell / drug therapy*
  • Carcinoma, Squamous Cell / immunology*
  • Carcinoma, Squamous Cell / pathology
  • Follow-Up Studies
  • Macrophages / immunology*
  • Macrophages / pathology
  • Mice
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Programmed Cell Death 1 Receptor / immunology
  • Pyrroles / pharmacology
  • Receptor, Macrophage Colony-Stimulating Factor / antagonists & inhibitors
  • Receptor, Macrophage Colony-Stimulating Factor / immunology
  • Retrospective Studies
  • Xenograft Model Antitumor Assays


  • Aminopyridines
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Pyrroles
  • pexidartinib
  • Receptor, Macrophage Colony-Stimulating Factor