LXR activation reduces immunosuppressive MDSCs to activate antitumor cytotoxic T cells.

  • Major finding: LXR activation reduces immunosuppressive MDSCs to activate antitumor cytotoxic T cells.

  • Mechanism: LXR agonism upregulates its transcriptional target ApoE, which binds to LRP8 to impair MDSC survival.

  • Impact: LXR agonists may relieve immunosuppression to enhance the efficacy of immune checkpoint blockade.

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Immune checkpoint inhibition has had success in some patients with cancer, but the majority of patients do not respond. Many of the nonresponding patients have high levels of circulating myeloid-derived suppressor cells (MDSC) that suppress the innate and adaptive immunity to suppress the antitumor immune response. Thus, strategies to target MDSCs might enhance the efficacy of immune checkpoint blockade. The Liver-X receptors (LXRβ and LXRα) are nuclear hormone receptor family transcription factors, and LXR agonists have been shown to inhibit tumorigenesis, with more potent antitumor effects in immune-competent mice. These findings prompted Tavazoie and colleagues to investigate the effects of LXR antagonism on the antitumor immune response using the LXRβ agonists GW3965 and RGX-104, which is currently being investigated in a phase I clinical trial. LXRβ agonism suppressed tumor growth in vivo in mice with lung, ovarian, renal cell, triple-negative breast, or colon cancer, melanoma, or glioblastoma. Further, LXR activation reduced the abundance of tumor-infiltrating and systemic MDSCs and increased tumor-infiltrating activated CD8+ and CD4+ T cells to reverse tumor immune evasion and promote antitumor immunity. Mechanistically, LXR agonism promoted upregulation of its transcriptional target ApoE, which bound to its receptor LRP8 on MDSCs to reduce MDSC survival. In addition to its activity as a single agent, RGX-104 enhanced the efficacy of anti–PD-1 therapy in multiple tumor models, conferring sensitivity to immune checkpoint blockade in poorly immunogenic resistant models. Peripheral blood samples were obtained from patients in the phase I trial of RGX-104, and these samples showed that LXR agonism depletes MDSCs and promotes T-cell activation in human cancer. Collectively, these findings suggest that LXR agonists may enhance the efficacy of immunotherapy in poorly immunogenic tumors by depleting MDSCs and support further investigation of RGX-104 in patients with cancer.

Tavazoie MF, Pollack I, Tanqueco R, Ostendorf BN, Reis BS, Gonsalves FC, et al. LXR/ApoE activation restricts innate immune suppression in cancer. Cell 2018;172:825–40.e18.

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