LXR/ApoE Activation Restricts Innate Immune Suppression in Cancer.
Cell
; 172(4): 825-840.e18, 2018 02 08.
Article
em En
| MEDLINE
| ID: mdl-29336888
ABSTRACT
Therapeutic harnessing of adaptive immunity via checkpoint inhibition has transformed the treatment of many cancers. Despite unprecedented long-term responses, most patients do not respond to these therapies. Immunotherapy non-responders often harbor high levels of circulating myeloid-derived suppressor cells (MDSCs)-an immunosuppressive innate cell population. Through genetic and pharmacological approaches, we uncovered a pathway governing MDSC abundance in multiple cancer types. Therapeutic liver-X nuclear receptor (LXR) agonism reduced MDSC abundance in murine models and in patients treated in a first-in-human dose escalation phase 1 trial. MDSC depletion was associated with activation of cytotoxic T lymphocyte (CTL) responses in mice and patients. The LXR transcriptional target ApoE mediated these effects in mice, where LXR/ApoE activation therapy elicited robust anti-tumor responses and also enhanced T cell activation during various immune-based therapies. We implicate the LXR/ApoE axis in the regulation of innate immune suppression and as a target for enhancing the efficacy of cancer immunotherapy in patients.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Apolipoproteínas E
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Células Supressoras Mieloides
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Receptores X do Fígado
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Imunidade Inata
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Neoplasias Experimentais
Limite:
Animals
Idioma:
En
Revista:
Cell
Ano de publicação:
2018
Tipo de documento:
Article