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

作者：Peranzoni, Elisa^*; Lemoine, Jean; Vimeux, Lene; Feuillet, Vincent; Barrin, Sarah; Kantari-Mimoun, Chahrazade; Bercovici, Nadage; Guerin, Marion; Biton, Jerome; Ouakrim, Hanane; Regnier, Fabienne; Lupo, Audrey; Alifano, Marco; Damotte, Diane; Donnadieu, Emmanuel^*

来源：Proceedings of the National Academy of Sciences, 2018, 115(17): E4041-E4050.

DOI：10.1073/pnas.1720948115

• cancer
• immunotherapy
• T cells
• macrophages
• migration

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.

• 出版日期2018-4-24