Journal
ONCOIMMUNOLOGY
Volume 8, Issue 7, Pages -Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/2162402X.2019.1596005
Keywords
ICOS; humanized mice; regulatory T cells; chemotherapy; immunotherapy; cyclophosphamide
Categories
Funding
- Ligue Nationale contre le cancer (LNC)
- Agence Nationale de la Recherche [ANR-11-EMMA-0045 VICIT]
- Glaxo Smith Kline (GSK)
- French Ministere de l'Education Superieure et de la Recherche
- LNC
- GSK
- Institut Universitaire de Cancerologie (Sorbonne Universite)
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Mice 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.gamma c-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. Depletion of human CD8(+) T cells or of murine myeloid cells marginally affected 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, opening new perspectives for the treatment of breast cancer. One sentence summary: Targeting ICOS in combination with chemotherapy is a promising strategy to improve tumor immunity in humans.
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