AG "Tumor Plasticity & Resistance in Melanoma" Head: Univ.-Prof. Dr. rer. nat. Iris Helfrich
Research Focus: Tumor Heterogeneity and Immune Cell Plasticity in Immune Checkpoint Therapy Resistance
Malignant melanoma (MM) remains one of the most aggressive and therapy-resistant cancers, largely due to tumor cell heterogeneity and immune cell plasticity, which critically shape the tumor microenvironment (TME) and influence treatment efficacy. While immune checkpoint inhibitors (ICIs) have revolutionized melanoma therapy, a significant proportion of patients exhibit primary or acquired resistance, underscoring the urgent need to better understand the cellular and molecular mechanisms driving these outcomes.
Our research focuses on two key aspects of therapy resistance:
Tumor Cell Plasticity and Heterogeneity – Melanoma cells can dynamically switch between different phenotypic states, enabling them to evade immune surveillance and resist targeted therapies. This process, termed phenotype switching, involves transcriptional and epigenetic reprogramming, allowing melanoma cells to transition between a differentiated, therapy-sensitive state and a dedifferentiated, invasive, and immune-resistant state.
Immune Cell Plasticity and Dysfunction – Infiltrating immune cells, particularly T cells, neutrophils, and macrophages, are highly plastic and can be reprogrammed by the tumor to adopt pro-tumorigenic functions, thereby limiting anti-tumor immunity and reducing ICI efficacy. Tumor-educated neutrophils, for instance, can suppress T cell function, while myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) create an immunosuppressive TME, further hindering therapy success.
Our overarching goal is to unravel how tumor-intrinsic mechanisms and immune cell plasticity collectively modulate the response to immune checkpoint therapy, contributing to therapy resistance. By identifying key regulatory pathways, we aim to develop novel therapeutic strategies that can enhance ICI response rates and overcome resistance mechanisms.
To address these challenges, we employ a multi-scale experimental approach, integrating:
- 2D/3D models & patient-derived systems to study tumor-stroma interactions.
- Xenotransplantation & genetic melanoma models to validate key findings.
- Intravital imaging & high-resolution microscopy to track immune-tumor dynamics in vivo.
In summary, we aim to identify strategies to reprogram the TME, enhance ICI efficacy, and overcome therapy resistance in melanoma.
Current Projects
- Molecular and functional analysis of tumor/stoma interactions controlling site-specific metastasis in MM
- Mechanisms of intrinsic and adaptive resistance to immune checkpoint inhibitors in MM
- Experimental modelling and functional analyses of melanoma brain metastases
- Clinical impact & biological function of the immune checkpoint protein CEACAM1
Current Funding
- Einfluss der Tumorzellplastizität auf Etablierung und Therapie von Hirnmetastasen des Malignen Melanoms“ –Neue Modelle, Neue Optionen-; Hiege Stiftung gegen Hautkrebs
- “DNA helicases in genome maintenance: from molecular and cellular mechanisms to specific inhibitors as potential drugs (AntiHelix)”; Horizon 2020, EU, Marie S. Curie Innovative Training Network
- “Unraveling the phenotypic coevolution of melanoma cells and neutrophils fostering metastasis and therapy resistance” ;DFG, Klinische Forscherguppe 337 “PhenoTImE” (no AoBJ: 655554)
- “Role of HSD11B1-mediated glucocorticoide activation in melanoma pathobiology and immunotherapy resistance”; Co-PI with M. Hölzel, UK Bonn; Deutsche Krebshilfe (no 70113168)
- “Preventing outgrowth of brain metastases under immunotherapy: Driving T-cells to the brain”; Co-PI with D. Schadendorf UKE Essen; Deutsche Krebshilfe „Priority Programm Translationale Onkologie“ (no 70112507)
Closed Funding (of the last 10 years)
- RIST - Ras Inhibition in soliden Tumoren; Horizon 2020 EU Life Sciences NRW (no 0800.951 LS-1-2-001d)
- “Identifizierung und therapeutische Validierung von NK-Zell-vermittelten „immune-escape“ Mechanismen bei der Etablierung zerebraler Melanommetastasen unter Einsatz des ersten, präklinischen Modells für spontane Hirnmetastasierung”; Monika Kutzner Stiftung
- “Tumorgenetisches Untersuchung von Hirnmetastasen des malignen Melanoms zur Identifizierung klinisch-relevanter Zielstrukturen“ -Präklinische Modelle versus klinische Situation-“; Hiege Stiftung gegen Hautkrebs
- “Erforschung der molekularen Grundlage des MIA-Proteins bei der Metastasierung im malignen Melanom”; Else Kröner-Fresenius Stiftung
- “Untersuchung der funktionellen Relevanz existierender Isoformen des Tumorsupressors CEACAM1 und deren klinisch Signifikanz beim malignen Melanom”; Hiege Stiftung gegen Hautkrebs
- “Recruitment of Tie2-macrophages to the tumor site: Impact on anti-angiogenic therapy resistance in malignant melanoma”; Melanoma International Foundation
- “Characterization of anti-VEGF-resistant, low-angiogenic tumor phenotypes in the spontaneous melanoma model MT/ret”; Industrial Support
- “Analysis of preventive and therapeutic effects of a new multi kinase inhibitor in the spontaneous melanoma model MT/ret”; Industrial Support
Univ.-Prof. Dr. rer. nat. Iris Helfrich
W2 Professor "Experimental Dermato-Oncology"
Head of Research
Head of "Tumor Plasticity & Resistance in Melanoma"
Mail: iris.helfrich@med.uni-muenchen.de
Phone: +49 (0) 89/440056003
Tara Bröker
MD student, PhD candidate
Phone: +49 (0) 89/440056024
Dr. rer. nat. Sara Egea-Rodriguez
Post-doc, Project coordinator
Mail: sara.rodriguez@med.uni-muenchen.de
Phone: +49 (0) 89/440056024
Meliss Perlin Gürsoy
MD, PhD candidate
Mail: melissa.guersoy@med.uni-muenchen.de
Phone: +49 (0) 89/440056024
Alumni LMU
Dr. rer. nat. Dayana Herrera-Rios (Post-doc)
Agnieszka Angelika Mach (MD student)
Juliane Klein (Bsc, Technician)
Defne Oktug (MD student, PhD candidate)
Siegfried Reitberger (MD student, PhD candidate FöFoLe)
Nathalia Ring (Technician)
Rebeca Schönherr (MD, PhD candidate)
Isabelle Werderitz (MD student, PhD candidate)
- Egea-Rodriguez S, Váraljai R, Nordmann TM, Lubis R, Philip M, Rambow F, Roesch A, Flaig M, Horn S, Stoll R, Zhao F, Paschen A, Klebl B, Hickson ID, Schadendorf D, Mann M, Helfrich I. RECQL4 affects MHC class II-mediated signaling and favors an immune-evasive signature that limits response to immune checkpoint inhibitor therapy in patients with malignant melanoma. Clin Transl Med. 2025 Jan;15(1):e70094. doi: 10.1002/ctm2.70094
- Placke JM, Bottek J, Váraljai R, Shannan B, Scharfenberg S, Krisp C, Spangenberg P, Soun C, Siemes D, Borgards L, Hoffmann F, Zhao F, Paschen A, Schlueter H, von Eggeling F, Helfrich I, Rambow F, Ugurel S, Tasdogan A, Schadendorf D, Engel DR, Roesch A. Spatial proteomics reveals sirtuin 1 to be a determinant of T-cell infiltration in human melanoma. Br J Dermatol. 2024 Dec 31:ljae433. doi: 10.1093/bjd/ljae433.
- Messmer JM, Thommek C, Piechutta M, Venkataramani V, Wehner R, Westphal D, Schubert M, Mayer CD, Effern M, Berghoff AS, Hinze D, Helfrich I, Schadendorf D, Wick W, Hölzel M, Karreman MA, Winkler F. T lymphocyte recruitment to melanoma brain tumors depends on distinct venous vessels. Immunity. 2024 Nov 12;57(11):2688-2703.e11. doi: 10.1016/j.immuni.2024.09.003.
- Váraljai R, Zimmer L, Al-Matary Y, Kaptein P, Albrecht LJ, Shannan B, Brase JC, Gusenleitner D, Amaral T, Wyss N, Utikal J, Flatz L, Rambow F, Reinhardt HC, Dick J, Engel DR, Horn S, Ugurel S, Sondermann W, Livingstone E, Sucker A, Paschen A, Zhao F, Placke JM, Klose JM, Fendler WP, Thommen DS, Helfrich I, Schadendorf D, Roesch A. Interleukin-17 signaling supports clinical benefit of dual CTLA-4 and PD-1 checkpoint inhibition in melanoma. Nat Cancer. 2023 Sep;4(9):1292-1308. doi: 10.1038/s43018-023-00610-2.
- Martins Nascentes Melo L, Herrera-Rios D, Hinze D, Löffek S, Oezel I,Turiello R, Klein J, Leonardelli S, Westedt IV, Al-Matary Y, Egea-Rodriguez S, Brenzel A, Bau M, Sucker A, Hadaschik E, Wirsdörfer F, Hanenberg H, Uhlenbrock N, Rauh D, Poźniak J, Rambow F, Marine JC, Effern M, Glodde N, Schadendorf D, Jablonska J, Hölzel M, Helfrich I. Glucocorticoid activation by HSD11B1 limits T cell-driven interferon signaling and response to PD-1 blockade in melanoma. J Immunother Cancer. 2023 Apr;11(4):e004150. doi: 10.1136/jitc-2021-004150.
- Karreman MA, Bauer AT, Solecki G, Berghoff AS, Mayer CD, Frey K, Hebach N, Feinauer MJ, Schieber NL, Tehranian C, Mercier L, Singhal M, Venkataramani V, Schubert MC, Hinze D, Hölzel M, Helfrich I, Schadendorf D, Schneider SW, Westphal D, Augustin HG, Goetz JG, Schwab Y, Wick W, Winkler F. Active Remodeling of Capillary Endothelium via Cancer Cell-Derived MMP9 Promotes Metastatic Brain Colonization. Cancer Res. 2023 Apr 14;83(8):1299-1314. doi: 10.1158/0008-5472.CAN-22-3964.
- Franklin C, Mohr P, Bluhm L, Grimmelmann I, Gutzmer R, Meier F, Garzarolli M, Weichenthal M, Pfoehler C, Herbst R, Terheyden P, Utikal J, Ulrich J, Debus D, Haferkamp S, Kaatz M, Forschner A, Leiter U, Nashan D, Kreuter A, Sachse M, Welzel J, Heinzerling L, Meiss F, Weishaupt C, Gambichler T, Weyandt G, Dippel E, Schatton K, Celik E, Trommer M, Helfrich I, Roesch A, Zimmer L, Livingstone E, Schadendorf D, Horn S, Ugurel S. Impact of radiotherapy and sequencing of systemic therapy on survival outcomes in melanoma patients with previously untreated brain metastasis: a multicenter DeCOG study on 450 patients from the prospective skin cancer registry ADOREG. J Immunother Cancer. 2022 Jun;10(6):e004509. doi: 10.1136/jitc-2022-004509.
- Chauvistré H, Shannan B, Daignault-Mill SM, Ju RJ, Picard D, Egetemaier S, Váraljai R, Gibhardt CS, Sechi A, Kaschani F, Keminer O, Stehbens SJ, Liu Q, Yin X, Jeyakumar K, Vogel FCE, Krepler C, Rebecca VW, Kubat L, Lueong SS, Forster J, Horn S, Remke M, Ehrmann M, Paschen A, Becker JC, Helfrich I, Rauh D, Kaiser M, Gul S, Herlyn M, Bogeski I, Rodríguez-López JN, Haass NK, Schadendorf D, Roesch A. Persister state-directed transitioning and vulnerability in melanoma. Nat Commun. 2022 Jun 1;13(1):3055. doi: 10.1038/s41467-022-30641-9.
- Bordbari S, Mörchen B, Pylaeva E, Siakaeva E, Spyra I, Domnich M, Droege F, Kanaan O, Lang KS, Schadendorf D, Lang S, Helfrich I, Jablonska J. SIRT1-mediated deacetylation of FOXO3a transcription factor supports pro-angiogenic activity of interferon-deficient tumor-associated neutrophils. Int J Cancer. 2022 Apr 1;150(7):1198-1211. doi: 10.1002/ijc.33871. Epub 2021 Nov 24.
- Michel L#, Helfrich I#, Hendgen-Cotta UB#, Mincu RI, Korste S, Mrotzek SM, Spomer A, Odersky A, Rischpler C, Herrmann K, Umutlu L, Coman C, Ahrends R, Sickmann A, Löffek S, Livingstone E, Ugurel S, Zimmer L, Gunzer M, Schadendorf D, Totzeck M, Rassaf T. Targeting early stages of cardiotoxicity from anti-PD1 immune checkpoint inhibitor therapy. Eur Heart J. 2022 Jan 31;43(4):316-329. doi: 10.1093/eurheartj/ehab430; # equally contributed
- Váraljai R, Horn S, Sucker A, Piercianek D, Schmitt V, Carpinteiro A, Becker KA, Reifenberger J, Roesch A, Felsberg J, Reifenberger G, Sure U, Schadendorf D, Helfrich I. Integrative Genomic Analyses of Patient-Matched Intracranial and Extracranial Metastases Reveal a Novel Brain-Specific Landscape of Genetic Variants in Driver Genes of Malignant Melanoma. Cancers (Basel). 2021 Feb 10;13(4):731. doi: 10.3390/cancers13040731.
- Herrera-Rios D, Mughal SS, Teuber-Hanselmann S, Pierscianek D, Sucker A, Jansen P, Schimming T, Klode J, Reifenberger J, Felsberg J, Keyvani K, Brors B, Sure U, Reifenberger G, Schadendorf D, Helfrich I. Macrophages/Microglia Represent the Major Source of Indolamine 2,3-Dioxygenase Expression in Melanoma Metastases of the Brain. Front Immunol. 2020 Feb 5;11:120. doi: 10.3389/fimmu.2020.00120.
- Ullrich N, Heinemann A, Nilewski E, Scheffrahn I, Klode J, Scherag A, Schadendorf D, Singer BB, Helfrich I. CEACAM1-3S Drives Melanoma Cells into NK Cell-Mediated Cytolysis and Enhances Patient Survival. Cancer Res. 2015 May 1;75(9):1897-907. doi: 10.1158/0008-5472.CAN-14-1752.
- Bald, T., Quast, T., Landsberg, J.,Rogava, M., Glodde, N., Lopez-Ramos, D., Kohlmeyer, J., Riesenberg, S., van den Boorn-Konijnenberg, D., Hömig-Hölzel, C., Reuten, R., Schadow, B., Weighardt, H., Wenzel, D., Helfrich, I., Schadendorf, D., Bloch, W., Bianchi, M., Koch, M., Fleischmann, K., Förster, I., Kastenmüller, W., Kolanus, W., Hölzel, M., Gaffal, E. and Tüting, T. Ultraviolet radiation-induced neutrophilic inflammation promotes angiotropism and metastasis in melanoma. Nature. 2014 Mar 6;507(7490):109-13. doi: 10.1038/nature13111.
- Hansen, W., Hutzler, M., Abel, S., Alter, C., Stockmann, C., Kliche, S., Albert, J., Sparwasser, T., Sakaguchi, S., Westendorf, A.M., Schadendorf, D., Buer, J.*, Helfrich, I.* Neuropilin 1 deficiency on CD4+Foxp3+ regulatory T cells impairs mouse melanoma growth. J Exp Med 2012 Oct 22;209(11):2001-16. doi: 10.1084/jem.20111497; * equally contributed
- Helfrich, I., Scheffrahn, I., Bartling, S., von Felbert, V., Weis, J., Middleton, M., Kato, M., Ergün, S., Schadendorf, D. Resistance to anti-angiogenic therapy is directed by vascular phenotype, vessel stabilization and maturation in malignant melanoma. J Exp Med 2010 Mar 15;207(3):491-503. doi: 10.1084/jem.20091846.
