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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.
Pubmed ID: 29336888 RIS Download
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Mus musculus with name C57BL/6J from IMSR.
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View all literature mentionsCell line U-251MG is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line GL261 is a Cancer cell line with a species of origin Mus musculus (Mouse)
View all literature mentionsCell line MDA-MB-468 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line LL/2 (LLC1) is a Cancer cell line with a species of origin Mus musculus
View all literature mentionsCell line NCI-H460 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line LN-229 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line OVCAR-3 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsMus musculus with name B6.129S7-Rag1tm1Mom/J from IMSR.
View all literature mentionsMus musculus with name C57BL/6J from IMSR.
View all literature mentionsMus musculus with name B6;129S6-Lrp8tm1Her/J from IMSR.
View all literature mentionsMus musculus with name B6.129P2-Apoetm1Unc/J from IMSR.
View all literature mentionsMus musculus with name B6;129S6-Nr1h3tm1Djm/J from IMSR.
View all literature mentionsMus musculus with name B6.Cg-Thy1a/Cy Tg(TcraTcrb)8Rest/J from IMSR.
View all literature mentionsMus musculus with name NOD.Cg-Prkdcscid/J from IMSR.
View all literature mentionsMus musculus with name B6;129S-Nr1h2tm1Djm/J from IMSR.
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