A novel combination of cyclophosphamide and anti-ICOS mAb prevents tumor growth by affecting regulatory T cells in mice with a human immune system

Mice reconstituted with a human immune system and bearing human tumors represent a promising model for developing novel cancer immunotherapy strategies. However, the nature of tumor infiltrating leukocytes in humanized mice and whether they can be mobilized to control tumor growth is currently unknown. Here, we used mass cytometry and multi parametric flow cytometry to characterize human leukocytes infiltrating a human breast cancer tumor model in CD34-reconstituted NOD.SCID.gc-null mice and compared it to breast cancer patient samples. We unambiguously detected human T cells, monocytes and plasmacytoid dendritic cells in the tumors of humanized mice. Importantly, activated/memory T cells and ICOS+ regulatory T cells were enriched in the tumor relative to the periphery both in humanized mice and in breast cancer patients. The presence of ICOS+ regulatory T cells in the tumor has been associated with poor survival in breast cancer patients. Administration of a neutralizing mAb to human ICOS reduced regulatory T cells, and a combination of the anti-ICOS mAb and chemotherapy reduced tumor growth whereas single treatments had no or little effects. Besides characterizing human leukocytes in tumors of humanized mice, we show that a combination of anti-ICOS and chemotherapy can mobilize human leukocytes to control tumor growth in vivo, making it a promising strategy in humans.