König and Schnurr Lab
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The immune system recognizes foreign molecular patterns (pathogen-associated molecular patterns, PAMPs) by virtue of its pattern recognition receptors (PRRs) to initiate a pathogen-directed immune response through the concerted release of alarm signals, attraction (via chemokines) and the activation of other immune cells. Due to the mechanistic overlap of an antiviral and antitumoral immune response the activation of viral RNA sensors, such as RIG-I-like helicases (RLH), can be leveraged to initiate an innate and adaptive immune response against tumors (Ellermeier et al., 2013; Poeck et al., 2008; Schnurr & Duewell, 2013). One advantage of RLHs over other pattern recognition receptors such as TLRs is that they are ubiquitously expressed in somatic cells as well as in tumor cells. Synthetic ligands – short double-stranded RNAs with a 5’-triphosphate group (3p-RNA) – can mimic a viral infection in the tumor tissue through targeted application. We have shown that RLH ligands can reprogram the immunosuppressive tumor microenvironment (TME) (Metzger et al, 2019) and mediate a T-cell mediated antitumoral immune response in solid (Helms et al, 2019) and non-solid (Ruzicka et al, 2020) preclinical tumor models. We further explore the additive and synergistic combination therapies with immune checkpoint inhibitors and adoptive cell therapy (in collaboration with AG Kobold) to increase therapeutic efficacy.
In addition to extrinsically applied RNAs, our group investigates mechanism by which endogenous double-strand RNA species are released during pathogenic cellular states that may induce an immune response against transformed or stressed cells.
Cytoplasmic double-stranded RNA released by many viruses during infection is sensed by RIG-I-like receptors (RLR). Activation of RLR signaling ultimately leads to induction of type I interferons (IFN), proinflammatory cytokines and cell death (Duewell et al, 2014). In contrast to the published mechanism of cell death induction, we found that RIG-I proximal signal does not induce cell death directly, but rather primes the cell for subsequent recognition of 3p-RNA by OAS1 that activates RNase L and leads to translational inhibition. Only the concerted action of RIG-I-dependent cell priming and RNase L-mediated translational inhibition induces tumor cell death upon 3p-RNA sensing (Boehmer et al, 2021). With this knowledge our goal is to modify the balance of immune activation by RIG-I and cell death induction (antigen release) via OAS/RNase L and investigate its effect on the efficacy to induce an antitumoral immune response. We further analyze how the differential activation of cytokine inducing nucleic acid sensing PRRs (RIG-I, MDA5, cGAS) and RNA sensors with direct antiviral effects (OAS/RNaseL, PKR, IFITs) that inhibit translation, influence the cell fate and immunological outcome of the RNA sensing event. This project is part of the SFB/TRR 237 „Nucleic Acid Immunity“.
Myeloid cells in the tumor microenvironment show a great variety of phenotypes, some of which pose an enormous hurdle to immunotherapies due to their suppressive effect on antitumoral effector cells. Especially pancreatic ductal adenocarcinoma (PDAC) shows a strong immunosuppressive phenotype with myeloid cells comprising most of the immune cells within the tumor microenvironment (TME) and correlating negatively with T cell infiltration and patient prognosis. We have shown earlier that RIG-I-based immunotherapy can partially overcome immunosuppression by reprogramming myeloid cells and attracting antitumoral T cells (Metzger et al, 2019). However, the knowledge of pro- and antitumoral myeloid cell subtypes is still too limited in order to fully exploit the therapeutic potential of modifying the myeloid cell compartment within the TME. With a combination of high-dimensional, machine learning-assisted phenotyping of myeloid subsets and functional assays, critical suppressive neutrophil and monocyte subpopulation will be characterized. The overall goal is to better understand the specific role of myeloid cell subtypes within the TME and to specifically target protumoral subpopulation for generating a more immune-permissive TME to fully leverage the potential of tumor immunotherapies.
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