P01.02 TLR-mediated suppression of the CCL22-CCR4 axis as a new target for tumor immunotherapy

Background Unmethylated CpG-DNA is a potent ligand for the endosomal Toll-like-receptor-9, important immune activation to pathogen-associated molecules. 1 CpG and other TLR-ligands show effective immunotherapeutic capacities in cancer treatment by inducing an antitumorigenic immunity. 2 They are able reduce tumor progression reduction of intratumoral secretion immunoregulating chemokine CCL22 3 subsequent recruitment immunosuppressive regulatory T cells (Treg), which express CCR4 only so far known receptor CCL22. 4 Our recent work has shown that dendritic (DC) lymph node, mediates tolerance DC-Treg contacts. 5 Indeed, absence CCL22, responses vaccination were stronger resulted rejection. 6 Therefore, we aiming investigate effects on systemic levels, elucidating all involved mechanisms identify new targets immunotherapy. Materials Methods T, B CD11c + DCs wildtype (wt) RAG1 -/- mice isolated from splenocytes magnetic-activated cell sorting vitro assays. Different co-cultures incubated with GM-CSF, as inducer. For vivo experiments, wt treated CpG, R484 or poly(I:C) alone combination GM-CSF. CCL22-levels number organs analyzed. Results Analyzing different compartments , found whole secrete during culture while DC cultured showed no secretion. When reduced splenocytes, it was induced alone. The same results seen when RAG lack functional cells, CpG. suppress unlike Co-cultures however, strongest suppression DC. In could TLR ligands tested significantly. Furthermore, even presence inducer Conclusions We mediate ligands. fact levels GM-CSF demonstrates suppressive capacity References O’Neill LA, et al . history toll-like receptors – redefining innate Nat Rev Immunol 2013; 13 (6):453–60. Rothenfusser S, Recent advances immunostimulatory oligonucleotides. Curr Opin Mol Ther 2003; (2):98–106. Wang Intratumoral injection oligonucleotide reverts resistance PD-1 blockade expanding multifunctional CD8+ cells. Proc Natl Acad Sci U S A 2016; 113 (46): E7240–E7249. Rapp M, controls immunity promoting communication nodes. J Exp Med 2019; 216 (5):1170–1181. Piseddu I, Constitutive expression mediated cell-derived 2020; 205 (8):2056–2065. Anz D, Suppression type i interferon inhibits migration blocks progression. Cancer Res 2015; 75 (21):4483–93. Disclosure Information J. Grün: None. I. Piseddu: C. Perleberg: N. Röhrle: S. Endres: D. Anz: