Clever-1 regulated immune responses for novel anti-cancer therapy
Miro Viitala. Reetta Virtakoivu, Sirpa Jalkanen and Maija Hollmén
Medicity Research Laboratory, Department of Clinical Microbiology and Immunology, Institute of Biomedicine, University of Turku, Turku, Finland
The progression of cancer depends on the quality and quantity of anti-tumor immune responses. Clever-1 (also known as Stabilin-1) is a multifunctional molecule conferring scavenging ability on a subset of alternatively activated macrophages and human monocytes. Recent publications suggest that Clever-1 mediates silent ligand clearance contributing to the modulation of the tumor microenvironment rather than to macrophage phenotype itself. Our data now shows that in fact Clever-1 has a fundamental role in modulating the pro-inflammatory responses on type II macrophages. Genetic ablation of Clever-1 on dexamethasone induced macrophages re-stimulated with LPS led to reduced phospho mTORC1 signaling and activated Nfkb signaling and TNF-α secretion. Interestingly, tumor hosts devoid of Clever-1 had increased populations of pro-inflammatory macrophages in both mouse mammary (E0771, 4T1) and lung (LLC) carcinomas. Combining anti-Clever-1 with anti-PD-1 but not with anti-PD-L1 had a synergistic inhibitory effect on tumor growth and metastasis to the lung and tumor-draining lymph nodes. Therefore, we believe that Clever-1 expression on type II macrophages supports their immunosuppressive phenotype and that Clever-1 is a potential therapeutic immune checkpoint molecule on macrophages.