Abstract 874: Lifting the iron curtain: Imaging cellular barriers to combination chelation-immune checkpoint therapy
Authors: Leftin Avigdor , Veeraperumal Suresh , Zhao Huiyong , Budhu Sadna , Stanchina Elisa de , Wolchok Jedd , Merghoub Taha , Koutcher Jason 
Published: July 2017

Abstract
Iron accumulation in cancer cells and macrophages can result in a tumor microenvironment that is unfavorable for checkpoint immune therapy. Chelation is a safe approach of reducing cellular iron accumulation that while affecting all cells biochemically, has been shown to also regulate tumor growth via specific “off-label” effects on macrophages that can hypothetically support an immune therapy responsive microenvironment. To further investigate the connection between infiltration of macrophages, iron chelation therapy, and synergy with immune therapy, we used established orthotopic Myc-CaP and TRAMP-C2 prostate cancer models and quantitative iron and cellular MRI, histology, and FACS to evaluate pre-treatment and post-chelation macrophage/immunological status, and MRI to monitor tumor growth. Quantitative assessment of cellular iron from MRI and histology of tumors, livers, and spleens revealed differences in tissue iron levels between host mouse strains, and enabled us to correlate these differences with extent of iron-macrophage infiltration in the tissues. To see if we could reduce these cells metabolically we administered the oral chelator deferiprone at tumor onset which resulted in reductions in endpoint tumor volume in both prostate tumor models with the largest response to chelation being observed in low-iron C57BL6 model backgrounds; a result subsequently confirmed in MMTV-PyMT orthotopic breast cancer models. Even in cases of complete tumor growth inhibition, systemic iron-load was not significantly affected, indicating that chelation achieved these therapeutic gains without harmful side-effects. Reduction of iron-macrophages and tumor volume accompanied shifts in macrophage surface receptor presentation and T-cell repertoire indicating that pro-tumor (M2) macrophage de-polarization to anti-tumor (M1) phenotypes occurred with chelation therapy. As these changes can potentially support improved action of checkpoint PDL-1 inhibitors, we then tested the combination chelation-checkpoint therapy approach in the prostate tumor models. These trials showed a modest reduction in tumor growth with either chelation or immune checkpoint therapy alone. A notable synergistic effect was observed using combination chelation-checkpoint therapy that accompanied a shift in macrophage polarization suggesting that chelation was sufficient to enhance checkpoint response. These therapeutic imaging studies demonstrate how tumor infiltration of iron-macrophages can be used as a biomarker of the immune-microenvironment, and how by using iron-chelation immunotherapeutic response can be enhanced.
Citation Format: Avigdor Leftin, Suresh Veeraperumal, Huiyong Zhao, Sadna Budhu, Elisa de Stanchina, Jedd Wolchok, Taha Merghoub, Jason Koutcher. Lifting the iron curtain: Imaging cellular barriers to combination chelation-immune checkpoint therapy [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 874. doi:10.1158/1538-7445.AM2017-874