Abstract
Triple-negative breast cancer (TNBC) is a highly aggressive subtype that is untreatable with hormonal or HER2-targeted therapies and is also typically unresponsive to checkpoint-blockade immunotherapy. Within the tumor microenvironment dysregulated immune cell metabolism has emerged as a key mechanism of tumor immune-evasion. We have discovered that the Liver-X-Receptors (LXRα and LXRβ), nuclear receptors known to regulate lipid metabolism and tumor-immune interaction, are highly activated in TNBC tumor associated myeloid cells. We therefore theorized that inhibiting LXR would induce immune-mediated TNBC-tumor clearance. Here we show that pharmacological inhibition of LXR activity induces tumor destruction primarily through stimulation of CD8+ T-cell cytotoxic activity and mitochondrial metabolism. Our results imply that LXR inverse agonists may be a promising new class of TNBC immunotherapies.
Highlights
Triple-negative breast cancer (TNBC) is a highly aggressive subtype that is untreatable with hormonal or HER2-targeted therapies and is typically unresponsive to checkpoint-blockade immunotherapy
NR1H3 expression strongly overlapped with that of ABCA1 (Fig. 1D,E) in these myeloid clusters. These findings implied that LXRα signaling was selectively upregulated in TNBC tumor resident myeloid cells and highlighted that LXR activation in immune cells may be relevant to tumor-immune interactions in TNBC
It is imperative that novel mechanisms of TNBC immunotherapy resistance are identified and exploited in order to engineer novel treatments
Summary
Triple-negative breast cancer (TNBC) is a highly aggressive subtype that is untreatable with hormonal or HER2-targeted therapies and is typically unresponsive to checkpoint-blockade immunotherapy. The Delgoffe group has shown that hypoxic conditions within tumors suppressed the metabolic activity of tumor-infiltrating immune cells and potentiated resistance to PD-1 treatment in melanoma models[7,15]. They went on to show that PD-1 resistance was pharmacologically targetable using glycolysis inhibition[15]. Their work highlighted that genetic or drug-mediated disruption of cholesterol synthesis had immune-mediated anti-tumor effects[16,17] These studies were the first to implicate the nuclear receptors, the Liver-X-Receptors α and β (NR1H3 and NR1H2), as molecular targets of these cholesterol metabolites and a central mediator of lipid-mediated immune suppression[8,16,17,18,19,20,21]. The efficacy of pharmacologically modulating LXR as an immunotherapeutic strategy, has not been tested in TNBC
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