Systemic Anti-Tumor Immune Responses
In cancer therapy, the goal is to achieve local control of the tumor with radiation therapy, either by causing the death of the cancer cells or by stopping their growth. With modern radiation technology and planning, it is possible to deposit a higher radiation dose per fraction in the tumor within hypofractionation protocols without increasing the burden on the surrounding normal tissue. Preclinical experiments increasingly suggest that this hypofractionated irradiation, in particular, induces immunogenic cell death and alters the tumor microenvironment to favor an antitumor immune response. Ideally, this immune response is then directed not only against the locally irradiated tumor, but also has systemic effects on metastases that may not yet have been diagnosed. However, the resulting decrease in tumor mass outside the irradiation field, also called the "abscopal effect," is rarely observed in the clinic.
Immunotherapies, such as tumor vaccines, have the potential to augment the anti-tumor immune responses elicited by radiotherapy or, in the case of immune checkpoint inhibitors, to counteract the immunosuppressive tumor microenvironment. Strikingly, reports of systemic (abscopal) effects have increased in recent years since radiotherapy has been increasingly combined with immunotherapies in the clinic, particularly in the context of clinical trials. Preclinical data support the synergy of radiation immunotherapies to induce abscopal effects.
In this group, the immunological basis of systemic (abscopal) effects is investigated in preclinical experiments with melanoma and breast cancer models. One approach within an IZKF junior project (J102: "cDC1s in abscopal effects and HHP vaccination" ) combines therefore hypofractionated irradiation with a high-pressure generated tumor cell vaccine and immune checkpoint inhibitors. Mechanistic analyses include comparison of immune cell infiltration and tumor microenvironment in irradiated and non-irradiated tumors. A particular focus is on tumor antigen presentation by dendritic cells. In addition, the impact of previously less explored immune checkpoint molecules on tumor immunosuppression is investigated.
Doctoral candidates - Medicine
Lisa Berger
Simon Gehre (IZKF)
Fridolin Grottker (IZKF)
Juliane Siegert (IZKF)
Tobias Dashi (IZKF)
Methods
Multicolor Flow Cytometry
Preclinical Model Systems
CRISPR gene editing
high hydrostatic pressure inactivation of tumor cells
RNA sequencing
(Endpoint) PCR
Quantitative PCR
ELISA
Primary Cell Cultures
MSD System (Multi-Array Technology)
Selected Publications
Gehre, S., Meyer, F., Sengedorj, A., Grottker, F., Reichardt, C. M., Alomo, J., Borgmann, K., Frey, B., Fietkau, R., Rückert, M., & Gaipl, U. S. (2023). Clonogenicity-based radioresistance determines the expression of immune suppressive immune checkpoint molecules after hypofractionated irradiation of MDA-MB-231 triple-negative breast cancer cells. Frontiers in oncology, 13, 981239. https://doi.org/10.3389/fonc.2023.981239
Wedekind H, Walz K, Buchbender M, Rieckmann T, Strasser E, Grottker F, Fietkau R, Frey B, Gaipl US, Rückert M. Head and neck tumor cells treated with hypofractionated irradiation die via apoptosis and are better taken up by M1-like macrophages. Strahlenther Onkol. 2022 Feb;198(2):171-182. doi.org/10.1007/s00066-021-01856-4.
Rückert M, Flohr AS, Hecht M, Gaipl US. Radiotherapy and the immune system: More than just immune suppression. Stem Cells. 2021 Sep;39(9):1155-1165. doi.org/10.1002/stem.3391
Rückert M, Deloch L, Frey B, Schlücker E, Fietkau R, Gaipl US. Combinations of Radiotherapy with Vaccination and Immune Checkpoint Inhibition Differently Affect Primary and Abscopal Tumor Growth and the Tumor Microenvironment. Cancers (Basel). 2021 Feb 9;13(4):714.
doi.org/10.3390/cancers13040714
Seitz C, Rückert M, Deloch L, Weiss EM, Utz S, Izydor M, Ebel N, Schlücker E, Fietkau R, Gaipl US, Frey B. Tumor Cell-Based Vaccine Generated With High Hydrostatic Pressure Synergizes With Radiotherapy by Generating a Favorable Anti-tumor Immune Microenvironment.Front Oncol. 2019 Aug 28;9:805.
doi.org/10.3389/fonc.2019.00805
Further publications of Dr. Michael Rückert available on "Web of Science Researcher ID".
Project-related third party funding
IZKF junior project leader: J102 “cDC1s in abscopal effects and HHP vaccination”
Cooperations
Prof. Dr. med. Dr. h.c. Friedrich Paulsen
Institut für Funktionelle und Klinische Anatomie, Friedrich-Alexander-Universität Erlangen-Nürnberg
Prof. Dr.-Ing. Schlücker
Lehrstuhl für Prozessmaschinen und Anlagentechnik, Friedrich-Alexander-Universität Erlangen-Nürnberg
Prof. Dr.-Ing. Michael Wensing
Department Chemie- und Bioingenieurwesen (CBI), Friedrich-Alexander-Universität Erlangen-Nürnberg