Retinoid X receptor agonist LG100268 modulates the immune microenvironment in preclinical breast cancer models

Ana S Leal,Kayla Zydeck,Lyndsey A Reich,Michael B Sporn,Karen T Liby,Sarah Carapellucci,Di Zhang,Jessica A Moerland

doi:10.1038/s41523-019-0135-5

Abstract

Despite numerous therapeutic advances in the past decade, breast cancer is expected to cause over 42,000 deaths in the United States in 2019. Breast cancer had been considered an immunologically silent tumor; however recent findings suggest that immune cells play important roles in tumor growth even in the breast. Retinoid X receptors (RXRs) are a subclass of nuclear receptors that act as ligand-dependent transcription factors that regulate a variety of cellular processes including proliferation and differentiation; in addition, they are essential for macrophage biology. Rexinoids are synthetic molecules that bind and activate RXRs. Bexarotene is the only rexinoid approved by the FDA for the treatment of refractory cutaneous T-cell lymphoma. Other more-potent rexinoids have been synthesized, such as LG100268 (LG268). Here, we report that treatment with LG 268, but not bexarotene, decreased infiltration of myeloid-derived suppressor cells and CD206-expressing macrophages, increased the expression of PD-L1 by 50%, and increased the ratio of CD8/CD4, CD25 T cells, which correlates with increased cytotoxic activity of CD8 T cells in tumors of MMTV-Neu mice (a model of HER2-positive breast cancer). In the MMTV-PyMT murine model of triple negative breast cancer, LG268 treatment of established tumors prolonged survival, and in combination with anti-PD-L1 antibodies, significantly (p = 0.05) increased the infiltration of cytotoxic CD8 T cells and apoptosis. Collectively, these data suggest that the use of LG268, a RXR agonist, can improve response to immune checkpoint blockade in HER2+ or triple-negative breast cancer.

Highlights

Breast cancer is the most frequently diagnosed cancer in the United States of America, claiming over 42,000 lives each year.[1]Numerous treatments have improved survival; aggressive subtypes, such as triple negative (TNBC) and epidermal growth factor receptor 2 (HER2)-positive breast cancer, are still challenging to treat and often deadly
Bars represent average and error bars the standard error of the mean (SEM). d Immunohistochemistry for cleaved caspase 3 and proliferating cell nuclear antigen (PCNA) in tumors
We explored the effects of LG268, an Retinoid X receptors (RXRs) agonist, as an immune modulator in the tumor microenvironment of two genetically and histologically distinct mouse models of breast cancer

Summary

INTRODUCTION

Breast cancer is the most frequently diagnosed cancer in the United States of America, claiming over 42,000 lives each year.[1]. Bexarotene treatment did not middle T oncoprotein (PyMT) in the mammary epithelium drives alter the percentage of infiltrating MDSCs compared with the the formation of aggressive tumors in the mammary gland of mice.[28] These highly aggressive tumors do not express progesterone, estrogen, or HER2 receptors and are unresponsive to conventional therapies, mirroring human TNBC.[30] control group in MMTV-Neu mice (Fig. 2a, d). No changes in the expression of pin macrophages and tumor-suppressive immune cell populations STAT3 or p-STAT5 were observed in whole tumor lysates from within the tumor microenvironment, creating a favorable milieu for the combination of appropriate RXR agonists with anti-PDL-1 antibodies.

RESULTS

DISCUSSION

Findings

METHODS