Reprogramming of myeloid-derived suppressor cells (MDSC) with RIG-I-like helicases to reinforce tumor therapy
Peter Duewell*, Sabrina V. Kirchleitner, Philipp Metzger, Lars König, Max Schnurr
Department of Clinical Pharmacology, Klinikum der Universität München, Germany
Tumors create a potent immunosuppressive network to evade the immune system from recognition and eradication. Mainly, these features include immunosuppressive cytokines (e.g. TGF‑b, IL-10), the infiltration of regulatory T cells (Treg) and cells of the myeloid lineage. Latter ones are rather immature cells including tumor-associated macrophages (TAM) or myeloid-derived suppressor cells (MDSC), originating from bone marrow-derived stem cells lacking further maturation under environmental tumor control. According to the monocytic (M-MDSC) or polymorph-nuclear (G-MDSC) morphology, MDSC bear a plethora of suppressive functions to promote tumor growth.
We could identify RIG-I-like helicases (RLH) to manipulate the tumor microenvironment with the result of inducing an immunogenic form of tumor cell death, with enhanced survival of mice with orthotopic pancreatic cancer. This ostensibly interferon-driven immune response was accompanied with reduced numbers of MDSC and RNA profiles revealed phenotypical changes of MDSC fractions from M2/G2 towards a M1/G1 phenotype. Ex vivo analysis of MDSC of RLH-ligand-treated tumor-bearing mice showed reduced capability to suppress T cell proliferation. Furthermore, T cells were enriched in the tumor tissue showing signs of enhanced effector function.
Breaking tumor-induced immune suppression is the major challenge in targeted therapies and aims at the reinforcement of a robust effector T cell function. We could show that RLH treatment led to reduced numbers of MDSC accompanied by a phenotype switch towards M1/G1, which correlated with enhanced effector T cell function. Thus, innovative concepts such as RLH-based immunotherapy of cancer provide a strategy to override the immunosuppressive tumor microenvironment, acting at multiple sites to unleash effective tumor control.
Funding: DFG DU1522/1-1, SFB 1123