Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 17, Pages E4041-E4050Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1720948115
Keywords
cancer; immunotherapy; T cells; macrophages; migration
Categories
Funding
- French Ligue Nationale contre le Cancer (Equipes labellisees)
- Plan Cancer (Tumor Heterogeneity and Ecosystem Program)
- Cancer Research for Personalized Medicine
- Fondation de France
- Associazone Italiana per la Ricerca sul Cancro
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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 longlasting interactions with CD8 T cells. Using a mouse tumor modelwith 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.
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