title: Cancer cell-derived IL-1α induces CCL22 and the recruitment of regulatory T cells.
abstract: In cancer patients, immunosuppression through regulatory T cells (Treg) is a crucial component of tumor immune evasion and contributes to disease progression. Tumor-infiltrating Treg in particular suppress local effector T cell responses and are associated with poor prognosis in tumors such as human pancreatic cancer or hepatocellular carcinoma (HCC). The chemokine CCL22 is known to recruit Treg into the tumor tissue and many types of human tumors are known to express high levels of CCL22. The mechanisms leading to intratumoral secretion of CCL22 are so far unknown. We demonstrate here that intratumoral CCL22 is induced in tumor-infiltrating immune cells through cancer cell-derived interleukin-1 (IL-1α). In pancreatic cancer and HCC, CCL22 is produced by intratumoral dendritic cells, while the cancer cells themselves do not secrete CCL22in vitroandin vivo. Incubation of human peripheral blood mononuclear cells (PBMC) or murine splenocytes with tumor cells or tumor cell supernatants strongly induced CCL22 secretionin vitro. Tumor cell supernatants contained IL-1 and CCL22 induction in PBMC could be specifically prevented by the IL-1 receptor antagonist anakinra or by transfection of tumor cell lines with IL-1 siRNA, leading to a suppression of Treg migration. In conclusion, we identify here tumor cell-derived IL-1α as a major inducer of the Treg attracting chemokine CCL22 in human cancer cells. Therapeutic blockade of the IL-1 pathway could represent a promising strategy to inhibit tumor-induced immunosuppression.
authors.affiliation: Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Klinikum der Universität München , Munich, Germany.
authors.forename: Gabriela Maria
authors.initials: GM
authors.lastname: Wiedemann
authors.affiliation: Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Klinikum der Universität München , Munich, Germany.
authors.forename: Max Martin Ludwig
authors.initials: MM
authors.lastname: Knott
authors.affiliation: Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Klinikum der Universität München , Munich, Germany.
authors.forename: Viola Katharina
authors.initials: VK
authors.lastname: Vetter
authors.affiliation: Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Klinikum der Universität München , Munich, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Rapp
authors.affiliation: Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Klinikum der Universität München , Munich, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Haubner
authors.affiliation: Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Klinikum der Universität München , Munich, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Fesseler
authors.affiliation: Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Klinikum der Universität München , Munich, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kühnemuth
authors.affiliation: Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Klinikum der Universität München , Munich, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Layritz
authors.affiliation: Medizinische Klinik und Poliklinik I, Klinikum der Universität München , Munich, Germany.
authors.forename: Raffael
authors.initials: R
authors.lastname: Thaler
authors.affiliation: Medizinische Klinik und Poliklinik III, Klinikum der Universität München , Munich, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Kruger
authors.affiliation: Department of Pathology, Ludwig-Maximilians-Universität , Munich, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Ormanns
authors.affiliation: Department of Pathology, Ludwig-Maximilians-Universität , Munich, Germany.
authors.forename: Doris
authors.initials: D
authors.lastname: Mayr
authors.affiliation: Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Klinikum der Universität München , Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Endres
authors.affiliation: Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany; Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Anz
keywords: CCL22; chemokine; interleukin-1; regulatory T cells; tumor