Journal
JOURNAL OF INVESTIGATIVE DERMATOLOGY
Volume 133, Issue 2, Pages 499-508Publisher
ELSEVIER SCIENCE INC
DOI: 10.1038/jid.2012.273
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Funding
- Fondation de France
- Association pour la Recherche sur le Cancer
- Institut National de la Sante et de la Recherche Medicale
- Ligue Contre le Cancer (Region Bourgogne)
- Fondation pour la Recherche Medicale
- Institut National du Cancer
- Ligue Nationale Contre le Cancer
- Agence Nationale pour la Recherche [ANR-10-PDOC-014-01]
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Dacarbazine (DTIC) is a cytotoxic drug widely used for melanoma treatment. However, the putative contribution of anticancer immune responses in the efficacy of DTIC has not been evaluated. By testing how DTIC affects host immune responses to cancer in a mouse model of melanoma, we unexpectedly found that both natural killer (NK) and CD8(+) T cells were indispensable for DTIC therapeutic effect. Although DTIC did not directly affect immune cells, it triggered the upregulation of NKG2D ligands on tumor cells, leading to NK cell activation and IFN gamma secretion in mice and humans. NK cell-derived IFN gamma subsequently favored upregulation of major histocompatibility complex class I molecules on tumor cells, rendering them sensitive to cytotoxic CD8(+) T cells. Accordingly, DTIC markedly enhanced cytotoxic T lymphocyte antigen 4 inhibition efficacy in vivo in an NK-dependent manner. These results underscore the immunogenic properties of DTIC and provide a rationale to combine DTIC with immunotherapeutic agents that relieve immunosuppression in vivo. Journal of Investigative Dermatology (2013) 133, 499-508; doi:10.1038/jid.2012.273; published online 6 September 2012
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