Abstract A17: An integrin agonist suppresses breast cancer by reducing CD11b+ leukocytes, promoting anti-tumor immunity

Abstract

Abstract Breast cancer remains the second highest cancer-related cause of death in women today. Neoadjuvant therapies reduce tumor size in patients but long-term survival remains poor. Tumor microenvironment shows a significant infiltration of CD11b+ tumor associated macrophages (TAMs) that promote tumor growth and metastases, while suppressing T-cell mediated anti-tumor immunity, suggesting that reducing infiltration of CD11b+ TAMs could have a therapeutic benefit. We recently developed a novel small molecule that targets CD11b+ cells and reduces their migration and tissue recruitment. Unlike previously described strategies, our methodology involves allosteric activation of CD11b, which induces transient increase in adhesion of CD11b+ cells to the vascular endothelium, thereby reducing the ability of the myeloid cells to transmigrate out of circulation and suppressing their recruitment into tumor and inflamed tissues. However, it is currently not known as to whether small molecule mediated CD11b activation can reduce TAM infiltration in tumors and whether that will have a therapeutic benefit. Here, we present results from studies with our lead compound leukadherin1 (LA1) in murine models of breast cancer. Our studies show that treatment of established syngeneic Cl66 orthotopic breast tumors in Balb/c mice with LA1 significantly reduces tumor growth and increases survival. LA1 treatment significantly reduced infiltration of CD11b+ cells into the tumor stroma, without affecting the levels of cells in circulation. LA1 treatment also significantly reduced expression of molecules that promote angiogenesis and tumor growth including MMP9, S100A8 and ARG1 that coincided with decreased CD31 and α-SMA, suggesting tumor vasculature disruption. Immune cell profiling revealed that LA1 treatment further promotes anti-tumor immunity by increasing the influx of cytotoxic CD8+ T cells into tumors. These data provide a rationale for using allosteric CD11b agonists to target TAM recruitment as a novel therapeutic approach for breast cancer. Citation Format: Samia Q. Khan, Mohd H. Faridi, Brian Ruffell, Ana M. S. Lopez, Shehryar Jehangir, Antonio J. Barbosa, Marta Torroella-Kouri, Lisa M. Coussens, Judith Varner, Vineet Gupta. An integrin agonist suppresses breast cancer by reducing CD11b+ leukocytes, promoting anti-tumor immunity. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A17.