Abstract 3966: Targeting integrin αvβ3-expressing cancer stem cells to manipulate tumor-associated macrophages

Tumor associated macrophages are involved in regulation of cancer growth and aggressiveness. Whereas M1 macrophages trigger an inflammatory response and inhibit tumor growth, M2 macrophages secrete pro-tumor cytokines into the microenvironment to support tumor progression. A macrophage switch from M1 to M2 has been associated with lung cancer progression, and cancer stem cells have been implicated as a driver of this reprogramming. We recently reported that integrin αvβ3 expression is induced on lung adenocarcinoma cells during drug resistance and is both necessary and sufficient to reprogram these tumors to a stem-like state. Given the role that cancer stem cells play in switching M1 to M2 macrophages, we asked whether αvβ3 expression on lung adenocarcinoma cells account for this macrophage conversion. The M1/M2 macrophage ratio in αvβ3-positive tumors was markedly decreased relative to tumors lacking αvβ3. We next treated mice bearing αvβ3-positive tumors with a monoclonal antibody (LM609) targeting this receptor to assess its ability to alter the macrophage phenotype within these tumors. LM609 was able to selectively eliminate the αvβ3-positive cancer stem cells via antibody-dependent cell-mediated cytotoxicity (ADCC), and this not only increased the M1 macrophage population, but also markedly enhanced the sensitivity of these tumors to the effects of therapy. These findings reveal that αvβ3-expressing cancer stem cells favor the pro-tumor M2 macrophage phenotype. Eliminating αvβ3-positive cancer stem cells via ADCC serves to both increase pro-inflammatory macrophages within the tumor microenvironment and prolong tumor sensitivity to therapy. Citation Format: Hiromi I. Wettersten, Toshiyuki Minami, Megan M. Kaneda, Laetitia Seguin, Judith A. Varner, Sara M. Weis, David A. Cheresh. Targeting integrin αvβ3-expressing cancer stem cells to manipulate tumor-associated macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3966. doi:10.1158/1538-7445.AM2017-3966