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How do SMAC mimetics+TNF Cause Immunogenic Cell Death?

Lochner, Marlene (2021) MOBN03 20202
Degree Projects in Molecular Biology
Popular Abstract
A LASTING ANTI-TUMOR RESPONSE

Cancer and its treatment have been a hot topic in research for quite a while. Despite, it being well researched, researchers still have not come up with one magic bullet. Will they ever though, is the question? Or should we be satisfied with several working treatments for individual cancers and patients? If we were only this far, since there are still some cancer types that we have no cure for yet, although there are many new targets for cancer treatment coming out.

In our study we have looked at compounds called SMAC mimetics (SM) which target proteins that inhibit apoptosis (IAPs) as shown in the figure. SM lead to the degradation of those IAPs and therefore, are able to induce cell death, namely... (More)
A LASTING ANTI-TUMOR RESPONSE

Cancer and its treatment have been a hot topic in research for quite a while. Despite, it being well researched, researchers still have not come up with one magic bullet. Will they ever though, is the question? Or should we be satisfied with several working treatments for individual cancers and patients? If we were only this far, since there are still some cancer types that we have no cure for yet, although there are many new targets for cancer treatment coming out.

In our study we have looked at compounds called SMAC mimetics (SM) which target proteins that inhibit apoptosis (IAPs) as shown in the figure. SM lead to the degradation of those IAPs and therefore, are able to induce cell death, namely apoptosis. There are several different modes of cell death. Apoptosis is believed to be silent and regulated, whereas necroptosis and pyroptosis are thought to induce an inflammatory response which is activating the immune system. Furthermore, as shown in the figure, the cytokine tumor necrosis factor (TNF) can signal through TNF receptor 1 (TNFR-1) stimulating cell death. Thus, we wondered how and if TNF or/and SMs can induce a type of cell death in cancer cells which is activating the immune system and eliciting a lasting immune response.

Different mouse tumor cell lines were utilized in our experiments to test them for sensitivity towards death upon TNF or SM treatment. To further define the cell death, we determined proteins involved by an inhibitor screen and by protein expression. This way, we observed that proteins involved in apoptosis were expressed upon SM+TNF treatment in cancer cell lines which died. To investigate if the mentioned treatment could induce a lasting anticancer response, experiments to determine immunogenicity were conducted. Results showed that upon SM+TNF treatment in one of the tested cancer cell lines the treatment could possibly induce immune activation through release of damage-associated molecular patterns. However, upon culturing the cancer cells with immune cells we could not see an increase in immune cell activation.

Immunogenic cell death and a lasting-cancer response are hard to be defined in an in vitro system as we used. However, in this isolated system it was easier to define modes of cell death and release of certain immunogenic stimulants. Nonetheless, to further find the characteristics of the cancer that decide if immunogenic cell death is induced or not upon SM+TNF treatment, other techniques might need to be applied. To transfer the gained knowledge to humans and cancer therapy a closed system such as animals, 3D organoids or organ-on-a-chip might be the mode of choice. As it seems from literature and our research, SM+TNF will also not present a magic bullet for inducing a lasting anti-tumor response.

Master’s Degree Project in Molecular Biology, 60 credits, 2021
Department of Biology, Lund University

Advisor: Prof. Dr. Lynn Wong
Institute of Experimental Immunology, University of Zurich (Less)
Please use this url to cite or link to this publication:
author
Lochner, Marlene
supervisor
organization
course
MOBN03 20202
year
type
H2 - Master's Degree (Two Years)
subject
language
English
id
9066645
date added to LUP
2021-10-13 11:19:29
date last changed
2021-10-13 11:19:29
@misc{9066645,
  author       = {{Lochner, Marlene}},
  language     = {{eng}},
  note         = {{Student Paper}},
  title        = {{How do SMAC mimetics+TNF Cause Immunogenic Cell Death?}},
  year         = {{2021}},
}