Macrophage-expressed small heterodimer partner impairs expansion of regulatory T cells and enhances immune checkpoint inhibition.

Breast cancer continues to be the second most common cancer-related mortality among women, providing strong rationale for the development of new therapeutic approaches. Cholesterol and its metabolism have been implicated in the progression of breast cancer. Specifically, elevated circulating cholesterol is a poor prognostic, while patients taking cholesterol-lowering drugs such as statins display increased recurrence-free survival time. In addition to cholesterol, various downstream metabolites play direct roles in promoting breast cancer growth and metastasis. Given the demonstrated importance of cholesterol and its metabolites in breast cancer pathophysiology, we hypothesized that proteins involved in the regulation of cholesterol homeostasis would play a role in cancer progression. A bioinformatics-based screen identified small heterodimer partner (SHP; NR0B2) as being associated with an increased time to recurrence. However, manipulation of this negative regulator of cholesterol metabolism within breast cancer cells did not alter proliferation or migration, suggesting that its protective role is likely conveyed through the tumor microenvironment. Macrophages were found to express SHP, and manipulation of SHP within macrophages resulted in altered expression of molecules associated with antigen presentation. Considering the clinical data indicating a protective role for SHP, it was somewhat paradoxical that its loss within macrophages resulted in an increased expansion of T cells. Upon further investigation, we found that this expansion was skewed towards regulatory T cells (Tregs). While immune therapies have revolutionized the treatment of certain cancers, their utility in breast cancer has been limited, especially outside of triple-negative disease. It has been postulated that this may be due to the highly immune-suppressive activities of certain myeloid and T-cell populations. Thus, reducing Treg infiltration or activity likely represents a rational way to enhance immune therapies. In this regard, SHP-knockout mice bred with the MMTV-PyMT model of mammary cancer displayed significantly enhanced tumor growth compared to SHP-replete mice. Likewise, orthotopic mammary tumor grafts grew at an increased rate in mice where SHP was selectively knocked out in cells of the myeloid lineage (SHPfl/fl;LysMCre), compared to controls. Importantly, treatment with a small-molecule agonist of SHP significantly enhanced the efficacy of anti-PD-L1 therapy in blocking the growth of an orthotopically grafted tumor, as well as in a model of metastatic mammary cancer. Collectively, our data highlight SHP as a modulator of Tregs, a cell population that has thus far been therapeutically intractable. By limiting Treg expansion and thus facilitating an anticancer immune response, SHP may represent a unique way to enhance the efficacy of immune checkpoint blockade. Funding: DOD BCRP BC171214 and NCI R01CA234025 (ERN), Lipstic Labex ANR-11-LABX-0021 (LA), Chateaubriand Fellowship (SHS). Citation Format: Sayyed Hamed Shahoei, Adam T. Nelson, Madeline A. Henn, Ashley E. Mathews, Joy J. Chen, Varsha Vembar, Liqian Ma, Lionel Apetoh, Erik R. Nelson. Macrophage-expressed small heterodimer partner impairs expansion of regulatory T cells and enhances immune checkpoint inhibition [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A93.