title: TLR7-based cancer immunotherapy decreases intratumoral myeloid-derived suppressor cells and blocks their immunosuppressive function.
abstract: Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells with the capacity to inhibit immunological responses. During cancer progression, MDSC are recruited to the tumor sites and secondary lymphoid organs, leading to the suppression of the antitumor function of NK and T cells. Here, we show that the TLR7/8 agonist resiquimod (R848) has a direct effect on MDSC populations in tumor-bearing mice. Systemic application of R848 led to a rapid reduction in both intratumoral and circulating MDSC. The subpopulation of monocytic MDSC (m-MDSC) was the most affected by R848 treatment with an up to 5-fold decrease in the tumor. We found that TLR7 stimulation in tumor-bearing mice led to a maturation and differentiation of MDSC with upregulation of the surface molecules CD11c, F4/80, MHC-I, and MHC-II. MDSC treated with R848 lost their immunosuppressive function and acquired instead an antigen-presenting phenotype with the capability to induce specific T-cell proliferation. Importantly, we found that MDSC co-injected s.c. with CT26 tumor cells lost their ability to support tumor growth after pretreatment with R848. Our results demonstrate that treatment of tumor-bearing mice with a TLR7/8 agonist acts directly on MDSC to induce their maturation and leads them to acquire a non-suppressive status. Considering the obstacles posed by MDSC for cancer immunotherapy, targeting these cells by a TLR7/8 agonist may improve immune responses against cancer.
authors.affiliation: Chair of Pharmacology, Department of Medicine, Faculty of Science, University of Fribourg , Fribourg, Switzerland.
authors.forename: Thibaud
authors.initials: T
authors.lastname: Spinetti
authors.affiliation: Chair of Pharmacology, Department of Medicine, Faculty of Science, University of Fribourg , Fribourg, Switzerland.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Spagnuolo
authors.affiliation: Chair of Pharmacology, Department of Medicine, Faculty of Science, University of Fribourg, Fribourg, Switzerland; Section of Pharmaceutical Sciences, Faculty of Science, and Department of Anesthesiology, Pharmacology and Intensive Care, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Inès
authors.initials: I
authors.lastname: Mottas
authors.affiliation: Chair of Pathology, Department of Medicine, Faculty of Science, University of Fribourg , Fribourg, Switzerland.
authors.forename: Chiara
authors.initials: C
authors.lastname: Secondini
authors.affiliation: Chair of Pharmacology, Department of Medicine, Faculty of Science, University of Fribourg , Fribourg, Switzerland.
authors.forename: Marina
authors.initials: M
authors.lastname: Treinies
authors.affiliation: Chair of Pathology, Department of Medicine, Faculty of Science, University of Fribourg , Fribourg, Switzerland.
authors.forename: Curzio
authors.initials: C
authors.lastname: Rüegg
authors.affiliation: Chair of Pharmacology, Department of Medicine, Faculty of Science, University of Fribourg , Fribourg, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Hotz
authors.affiliation: Chair of Pharmacology, Department of Medicine, Faculty of Science, University of Fribourg, Fribourg, Switzerland; Section of Pharmaceutical Sciences, Faculty of Science, and Department of Anesthesiology, Pharmacology and Intensive Care, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Carole
authors.initials: C
authors.lastname: Bourquin
keywords: Immunotherapy; MDSC; R848; TLR7; myeloid-derived suppressor cells