A novel combination of chemotherapy and immunotherapy controls tumor growth in mice with a human immune system

AbstractMice reconstituted with a human immune system and bearing human tumors represent a promising model for developing novel cancer immunotherapies. Here, we used mass cytometry and multi-parametric flow cytometry to characterize human leukocytes infiltrating a human breast cancer tumor model in immunocompromised NOD.SCID.γc-null mice reconstituted with a human immune system and compared it to samples of breast cancer patients. We observed highly activated human CD4+and CD8+T cells in the tumor, as well as minor subsets of innate immune cells in both settings. We also report that ICOS+CD4+regulatory T cells (Treg) were enriched in the tumor relative to the periphery in humanized mice and patients, providing a target to affect Treg and tumor growth. Indeed, administration of a neutralizing mAb to human ICOS reduced Treg proportions and numbers and improved CD4+ T cell proliferation in humanized mice. Moreover, a combination of the anti-ICOS mAb with cyclophosphamide reduced tumor growth, and that was associated with an improved CD8 to Treg ratio. However, depletion of human CD8+T cells only marginally affected tumor control whereas depletion of murine myeloid cells abrogated the effect of the combination therapy. Altogether, our results indicate that a combination of anti-ICOS mAb and chemotherapy controls tumor growth in humanized mice and highlight the crucial implication of innate immunity in treatment efficacy, opening new perspectives for the treatment of breast cancer.One sentence summaryICOS expressed on Tregs is a promising target to improve tumor immunity in humansAbbreviationsICOSInducible CostimulatoryNSGNOD.SCID.gc-nullTregregulatory T cellsCTXcyclophosphamideHuMicehumanized miceCyTOFcytometry time-of-flighttSNEtdistributed stochastic neighbor embeddingpDCsplasmacytoid dendritic cellsDCdendritic cellsICDimmunogenic cell death