Abstract 4744: Disruption of Clever-1 in macrophages activates the innate immune response and mediates tumor rejection

Macrophages are considered the main obstacles for successful cancer treatment since they can dampen anti-tumor immune responses and promote tumor progression and resistance formation. Macrophages are highly eligible candidates for targeted therapies since these cells are abundantly present in various tumors, they are very plastic and can be converted into pro-inflammatory macrophages supporting T cell activation and tumor rejection. Clever-1 (also known as Stabilin-1) is a multifunctional molecule conferring scavenging ability on a subset of alternatively activated macrophages. The aim of this study is to uncover previously unknown functions of Clever-1 in the regulation of macrophage-mediated anti-tumor immune responses and develop anti-Clever-1 therapy into clinical use for those suffering from refractory, untreatable solid tumors. By using in vivo tumor models and sophisticated immunological assays, our data show that mice carrying a macrophage-specific genetic deletion of Clever-1 (Lyz2-Cre/Stab1 fl/fl ) reject implanted Lewis lung carcinoma and EL4 lymphoma tumors. Macrophage Clever-1 deficiency induced proliferation of Ly6C hi monocytes in the tumor microenvironment but impaired their maturation and polarization into tumorigenic Ly6C lo macrophages. Tumors in Lyz2-Cre/Stab1 fl/fl mice consisted almost completely of proliferating CD8 T cells with an exhausted PD-1 + Lag3 + phenotype two weeks after implantation. Functionally, Clever-1 depleted macrophages showed enhanced pro-inflammatory responses following TLR activation with a shift in IL-12/IL-10 secretion levels. This was due to enhanced activation of mTORC1 and NFκB signaling, which resulted in increased secretion of TNFα in steady state and after LPS induction. In conclusion, our data show an important function of Clever-1 in controlling macrophage mediated local immune responses. Moreover, our data supports Clever-1 targeting as a novel approach to increase host defenses against immune compromised tumors and promotes anti-Clever-1 immunotherapy into clinical trials where it may have benefits in comparison with currently available immune activating drugs. Citation Format: Miro Viitala, Reetta Virtakoivu, Sina Tadayon, Sirpa Jalkanen, Maija Hollmen. Disruption of Clever-1 in macrophages activates the innate immune response and mediates tumor rejection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4744.