OR05-01 Small Heterodimer Partner Modulates Antigen Presenting Myeloid Cells to Impair Regulatory T Cell Expansion, Promoting Anti-Tumor Immunity in Models of Breast Cancer

Abstract

Immune checkpoint blockade has had underwhelming responses in breast cancer, in part due to the highly immune suppressive microenvironment. As a result, breast cancer continues to be the second most common cancer-related mortality amongst women, providing strong rationale for the development of new therapeutic approaches. Elevated circulating cholesterol is a poor prognostic, while breast cancer patients taking cholesterol-lowering drugs display increased time to recurrence. We and others have previously demonstrated that cholesterol metabolites mediate these effects by promoting breast cancer growth and metastasis, in part by suppressing the immune system. Therefore, given the demonstrated importance of cholesterol and its metabolites in breast cancer pathophysiology and immunology, we hypothesized that proteins involved in the regulation of cholesterol homeostasis would influence cancer progression. Through informatics analysis of breast tumors, we found that elevated expression of Small Heterodimer Partner (SHP; NR0B2) was a favorable prognostic. Antigen presenting cells such as macrophages and dendritic cells were found to express SHP, and manipulation of SHP altered the expression of genes involved in cross-talk with T cells. Intriguingly, when activated T cells were co-cultured with macrophages overexpressing SHP, there was a decrease in the expansion of regulatory T cells (Tregs) and vice versa in the absence of SHP. Adoptive transfer studies confirmed that loss of SHP resulted in immune suppressive Tregs. We hypothesized that myeloid cell-expressed SHP would promote immune surveillance and tumor clearance. In support of this hypothesis, tumors in the MMTV-PyMT model of mammary cancer grew at an accelerated rate in SHP-knockout mice. Tumors from these mice had significantly more Tregs and fewer effector T cells. Furthermore, orthotopic mammary tumor grafts grew at an increased rate in mice lacking SHP expression in myeloid cells (SHPfl/fl;LysMCre), compared to controls. A small molecule agonist of SHP impaired primary and metastatic tumor growth, and significantly enhanced the efficacy of immune checkpoint blockade in murine models of mammary cancer. Therefore, SHP represents a potential target to decrease suppressive Tregs, thereby allowing for immune-clearance of tumors.