König and Schnurr Lab
Cancer Vaccine Lab
Dr. rer. nat. Lars König
Prof. Dr. med. Max Schnurr
Our research focuses on deciphering fundamental mechanisms of innate immunity in the context of tumors. We aim to translate these findings into novel immunotherapeutic strategies by modulating immune activation and immune suppression pathway.
Networks & Doctoral Programs
We are part of the international training program of the Elitenetzwerk Bayern:
i-Target (immunotargeting of cancer)
Structured medical doctoral program
„Förderung für Forschung und Lehre“ (Föfole)
associated to the Transregio (TRR) 237 interdisciplinary research network „Nucleic Acid Immunity"
Our lab studies aspects of the innate immune system in the context of tumor immunotherapy. Our rationale is:
- The initiation of a de novo immune response against tumors by triggering pattern recognition receptors of the innate immune system (in situ vaccination)
- Tumor-myeloid cell network – understanding and targeting the immunosuppressive myeloid cell network within the tumor microenvironment
The overarching goal is to better understand basic mechanisms of innate immunity in order to use these findings to develop
innovative, synergistic tumor immunotherapies.
Activation of RNA sensing pathways for the immunotherapy of tumors – in situ vaccination
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.
Mechanism of dsRNA-induced tumor cell death
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.
Tumor - myeloid cell interaction and immunosuppressive mechanisms in the tumor micronenvironment
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.
Top Ten Papers
Doctoral students as co-authors are underlined (starting in 1998)
* equal contribution, # corresponding author
Stazzoni S, Böhmer D, Hernichel F, Özdemir D, Pappa A, Drexler D, Bauernfried S, Witte G, Wagner M, Veth S, Hopfner KP, Hornung V, König LM, Carell T.
Novel poxin stable cGAMP-derivatives are remarkable STING agonists.
Angewandte Chemie 2022; 10:e202207175.
Boehmer D, Formisano S, de Oliveira Mann C, Mueller S, Kluge M, Metzger P, Rohlfs M, Hörth Ch, Kocheise L, Lichtenthaler S, Hopfner KP, Endres S, Rothenfusser S, Friedel C, Duewell P, Schnurr* M, Koenig* L.
OAS1/RNase L executes RIG-I ligand-dependent tumor cell apoptosis.
Science Immunology 2021; 61, eabe2550.
Magg* Th, Okano* T, Koenig* L, Boehmer D, Schwartz S, Inoue K, Heimall J, Licciardi F, Ley-Zaporozhan J, Ferdman R, Park E, Calderon B, Dey D, Kanegane H, Cho K, Montin D, Reiter K, Griese M, Albert M, Rohlfs M, Gray P, Walz C, Conn G, Sullivan K, Klein Ch, Morio* T, Hauck* F.
Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency.
Science Immunology 2021; 60, eabf9564.
Lesch S, Blumenberg V, Stoiber S, Gottschlich A, Ogonek J, Cadilha B, Dantes Z, Rataj F, Dorman K, Lutz J, Karches C, Heise C, Kurzay M, Larimer B, Grassmann S, Rapp M, Nottebrock A, Kruger S, Tokarew N, Metzger P, Hoerth Ch, Benmebarek MR, Dhoqina D, Gruenmeier R, Seifert M, Oener A, Umut Ö, . . . Rothenfusser S, Duewell P, Koenig L, Schnurr M, Subklewe M, Liss A, Halama N, Reichert M, Mempel T, Endres S, Kobold S.
T cells armed with C-X-C chemokine receptor type 6 enhance adoptive cell therapy for pancreatic tumours
Nature Biomedical Engineering 2021; 35:2243-2257.
Boehmer D, Koehler L, Magg T, Metzger P, Rohlfs M, Ahlfeld J, Rack-Hoch A, Reiter K, Albert M, Endres S, Rothenfusser S, Klein Ch, Koenig L, Hauck F.
A novel complete autosomal recessive STAT1 LOF variant causes immunodeficiency with hemophagocytic lymphohistiocytosis-like hyperinflammation.
The Journal of Allergy and Clinical Immunology 2020; 8:3102-3111.
Ruzicka M, König L, Formisano S, Boehmer D, Vick B, Heuer EM, Meinl H, Kocheise L, Zeitlhoefler M, Ahlfeld J, Kobold S, Endres S, Subklewe M, Duewell P, Schnurr M, Jeremias I, Lichtenegger F, Rothenfusser S.
RIG-I-based immunotherapy enhances survival in preclinical AML models and sensitizes AML cells to checkpoint blockade.
Leukemia 2020; 34:1017-1026.
Koenig L#, Boehmer D, Metzger P, Schnurr M, Endres S, Rothenfusser S.
Blocking inflammation on the way: rationale for CXCR2 antagonists for the treatment of COVID-19.
Journal of Experimental Medicine 2020; 217:e20201342.
Metzger P, Kirchleitner S, Boehmer D, Hörth Ch, Eisele A, Ormanns S, Gunzer M, Lech M, Lauber K, Endres S, Duewell P, Schnurr M, König L.
Systemic but not MDSC-specific IRF4 deficiency promotes an immunosuppressed tumor microenvironment in a murine pancreatic cancer model.
Cancer Immunology, Immunotherapy 2020; 69:2101-2112.
Metzger P, Kirchleitner S, Kluge M, Koenig L, Hoerth Ch, Rambuscheck CA, Boehmer D, Ahlfeld J, Kobold S, Friedel C, Endres S, Schnurr M, Duewell P.
Immunostimulatory RNA leads to functional reprogramming of myeloid-derived suppressor cells in pancreatic cancer.
Journal for Immunotherapy of Cancer 2019; 7:288.
Helms M, Jahn-Hofmann K, Gnerlich F, Metz-Weidmann Ch, Braun M, Dietert G, Scherer P, Grandien K, Theilhaber J, Cao H, Wagenaar T, Schnurr M, Endres S, Wiederschain D, Scheidler S, Rothenfusser S, Brunner B, Koenig L.
Utility of the RIG-I agonist triphosphate RNA for melanoma therapy.
Molecular Cancer Therapeutics 2019; 18:2343-2356.