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
; 115(17): E4041-E4050, 2018 04 24.
Article
em En
| MEDLINE
| ID: mdl-29632196
ABSTRACT
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.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Carcinoma de Células Escamosas
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Linfócitos T CD8-Positivos
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Receptor de Morte Celular Programada 1
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Macrófagos
Tipo de estudo:
Observational_studies
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Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article