Abstract P6-05-01: The small heterodimer partner in macrophages reduces expansion of regulatory T cells and enhances immune checkpoint inhibition in breast cancer
Authors: Nelson Erik R. , Shahoei Sayyed Hamed , Nelson Adam T , Henn Madeline A , Mathews Ashley E , Chen Joy J , Vembar Varsha , Ma Liqian , Apetoh Lionel 
Published: March 2020

Abstract
It has become clear that cholesterol metabolism and homeostasis play significant roles 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. Preclinical and clinical work has established that 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. Therefore, we performed an informatics screen to identify those regulatory proteins associated with breast cancer progression. We focused on nuclear receptors due to their well-defined ligand-binding pocket and thus their proclivity to drug intervention. Our screen revealed that increased expression of Small Heterodimer Partner (SHP; NR0B2) was associated with an increased time to recurrence. However, manipulation of SHP 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). On the other hand, overexpression of SHP resulted in decreased expansion of Tregs. The immune-suppressive activity of the resulting Tregs was confirmed in subsequent assays. 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 speculated 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 strongly support a role for SHP in reducing the progression of breast cancer by limiting Treg expansion, thereby facilitating an anti-cancer immune response. As this nuclear receptor is amenable to small molecule intervention, SHP may represent a unique way to enhance the efficacy of immune checkpoint blockade.
This study was funded in part by awards to ERN from the DOD BCRP (BC171214) and NCI (R01CA234025), to LA from the French National Research Agency Lipstic Labex (ANR-11-LABX-0021), and a STEM Chateaubriand Fellowship to SHS from the Embassy of France in the United States.
Citation Format: Erik R. Nelson, Sayyed Hamed Shahoei, Adam T Nelson, Madeline A Henn, Ashley E Mathews, Joy J Chen, Varsha Vembar, Liqian Ma, Lionel Apetoh. The small heterodimer partner in macrophages reduces expansion of regulatory T cells and enhances immune checkpoint inhibition in breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-05-01.