Cancer Immunotherapy

Mission

To uncover the mechanisms that allow cancer cells to resist therapy and immune attack, and translate these discoveries into repurposed drugs and improved immunotherapies that transform outcomes for patients with cancer.

Research Focus

The group studies how cancer cells evade therapy and immune attack, using this knowledge to repurpose existing drugs into new, mechanism-guided treatment strategies. The work centers on proteostasis — the cellular system that maintains protein folding, degradation, and quality control — as a critical, underexplored driver of both chemotherapy and immunotherapy resistance. In multiple myeloma, the team showed that cells surviving therapy coordinate a rewiring of proteasome activity, mitochondrial metabolism, redox balance, membrane composition, and protein folding pathways, rather than relying on a single resistance mechanism. Building on these insights, the group is now extending its work to immunotherapy resistance in cancer to understand how tumor cells withstand and adapt to cytotoxic immune attack.

Key Research Questions

Which adaptations allow cancer cells to survive therapy-induced or immune-induced stress?
Can clinically approved or repurposed drugs be used to disrupt these adaptive mechanisms and resensitize resistant tumors?
How can insights into tumor protein homeostasis be leveraged to improve the efficacy and durability of immunotherapy?

Approach & Integration

These questions are addressed using functional genomics, chemical biology, and multi-omics approaches (proteomics, metabolomics, single-cell transcriptomics) in human cancer models. Methodologies include CRISPR-based screening, proteasome activity-based probes, and human immune cell co-culture systems

Specialized Expertise & Technology

Human immune–tumor co-culture models: alloreactive and autologous CTL platforms for modelling of resistance.
Functional genomics and CRISPR screening: genome-wide and targeted CRISPR knockout/knock-in approaches.
Multi-omics profiling: proteomics, metabolomics, transcriptomics, and single-cell RNA sequencing to map resistance trajectories and adaptive signaling networks.
Proteasome and proteostasis biology: functional characterization of 20S/26S proteasome and immunoproteasome activity, proteasome activity-based probes, and live-cell stress-response reporters for UPR/ISR/HSR pathway activation.
Drug repurposing pipeline: systematic screening and mechanistic validation of clinically approved compounds for repositioning against resistant cancer.
In vivo modeling: NSG mouse xenograft systems combining human tumor cells and immune effectors to validate resistance and therapeutic mechanisms in vivo.

No description

Research Group Leader

Mgr. Lenka Bešše, Ph.D.

Role

Junior Research Group Leader, Lenka Bešše Research Group

Contact Information

Office:

Bldg. A19/218, Kamenice 753/5, 625 00 Brno

Phone:

+420 549 493 546

Email:

lenka.besse@med.muni.cz

Selected Publications

Ferguson ID, Patiño-Escobar B, Tuomivaara ST, Lin YT, Nix MA, Leung KK, Kasap C, Ramos E, Nieves Vasquez W, Talbot A, Hale M, Naik A, Kishishita A, Choudhry P, Lopez-Girona A, Miao W, Wong SW, Wolf JL, Martin TG 3rd, Shah N, Vandenberg S, Prakash S, Besse L, Driessen C, Posey AD Jr, Mullins RD, Eyquem J, Wells JA, Wiita AP. The surfaceome of multiple myeloma cells suggests potential immunotherapeutic strategies and protein markers of drug resistance. Nat Commun. 2022 Jul 15;13(1):4121. doi: 10.1038/s41467-022-31810-6
Purde MT, Cupovic J, Palmowski YA, Makky A, Schmidt S, Rochwarger A, Hartmann F, Stemeseder F, Lercher A, Abdou MT, Bomze D, Besse L, Berner F, Tüting T, Hölzel M, Bergthaler A, Kochanek S, Ludewig B, Lauterbach H, Orlinger KK, Bald T, Schietinger A, Schürch CM, Ring SS, Flatz L. A replicating LCMV-based vaccine for the treatment of solid tumors. Mol Ther. 2024 Feb 7;32(2):426-439. doi: 10.1016/j.ymthe.2023.11.026
Våtsveen TK, Giliberto M, Bjornsdottir V, Centonze F, Besse A, Frey Y, Skånland SS, Tveita A, Alirezaylavasani A, Imbery JF, Misund K, Reiterer V, Zahoor M, Driessen C, Besse L, Tasken K, Schjesvold FH, Farhan H, Munthe LA. Targeting proteostasis in multiple myeloma through inhibition of LTK. Leukemia. 2025 Sep;39(9):2237-2245. doi: 10.1038/s41375-025-02682-8
Besse A, Kraus M, Totu T, Buljan M, Janssen APA, Van der Stelt M, Matisikova K, Veprkova J, Sedlarikova L, Jurinakova T, Truger M, Haferlach C, Lopez MM, Kortum MK, Rasche L, Driessen C, Besse L. Ceritinib overcomes proteasome inhibitor resistance in multiple myeloma by suppressing the protein folding response. Haematologica. 2025 Dec 11. doi: 10.3324/haematol.2025.289245
Rieger L, Irlinger K, Füchsl F, Tietje M, Purcarea A, Barbian N, Faber M, Vogelsang C, Pfeuffer L, Stotz S, Karpiuk O, Schulze T, Augsburger A, Glaisner N, Konetzki V, Friedel S, Besse A, Besse L, Driessen C, Buchner M, Schwamborn K, Steiger K, Giansanti P, Theurich S, Waldschmidt J, Kortüm KM, Hudecek M, Einsele H, Högner M, Kuster B, Krackhardt AM, Hecker JS, Bassermann F. Boosting CAR T-cell efficacy by blocking proteasomal degradation of membrane antigens. Blood. 2026 Jan 29;147(5):534-546. doi: 10.1182/blood.2024027616

Patents

ALK INHIBITORS FOR TREATMENT OF ALK-NEGATIVE CANCER AND PLASMA CELL-MEDIATED DISEASES (Patent No: WO2021083555) | Inventors: Hesso Farhan, Ludvig Munthe, Kjetil Tasken, Sigrid Skaland, Mariaserena Giliberto, Fredrik Hellen Schjesvold, Christoph Driessen, Lenka Besse, Andrej Besse | Patent Agency: World Intellectual Property Organization

Grant Projects

Investigation of proteasome inhibition combined with tyrosine kinase inhibition as a therapeutic option for triple-negative breast cancer treatment (NW26-03-00110) | Mgr. Lenka Bešše, Ph.D., Faculty of Medicine | Project Period: 1/2026 — 12/2029 | Investor: Ministry of Health of the CR / Ministry of Health Research Programme 2020 - 2026
CRISPR Activation Screening to Identify Surface Proteins Modulating Cytotoxic T Cell Responses in Multiple Myeloma (NW26J-03-00064) | Mgr. Andrej Bešše, Dr. sc. nat., Faculty of Medicine | Project Period: 1/2026 — 12/2029 | Investor: Ministry of Health of the CR / Ministry of Health Research Programme 2020 – 2026
ECPAS-Mediated Proteasome Remodeling as a Mechanism of Resistance to Proteasome Inhibition in Multiple Myeloma (26-21116S) | Mgr. Lenka Bešše, Ph.D., Faculty of Medicine | Project Period: 1/2026 — 12/2028 | Investor: Czech Science Foundation

Collaboration

Institute of Organic Chemistry, Leiden University, The Netherlands – Prof. Herman Overkleeft
iProtics, Leiden, The Netherlands – Dr. Elmer Maurits
Universitätsklinikum Würzburg, Germany – Prof. Dr. Martin Kortüm and Prof. Dr. Leo Rasche
University of Florida, Gainesville, Florida, USA – Dr. Amin Sobh
CHUV, Lausanne, Switzerland – Prof. Dr. Holger Auner
National Institute for Cancer Research (project funded from program EXCELES) - collaboration within NICR