Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Actin cytoskeleton remodeling protects tumor cells against immune attack

24.10.2018

Cancer cells have evolved multiple escape strategies to circumvent the body’s immune defenses such as the attack by Natural Killer (NK) cells which normally swiftly kill abnormal cells by releasing cytotoxic products. While studying breast cancer cell lines, Dr. Clément Thomas’ research team at the Luxembourg Institute of Health (LIH) uncovered a previously unknown mechanism that leaves tumor cells unharmed by NK cell-mediated cytotoxicity. The scientists published their findings in the August issue of the acclaimed scientific journal “Cancer Research”.

The Laboratory of Experimental Cancer Research at LIH’s Department of Oncology conducts clinically oriented research aiming at understanding how cancer cells evolve progressively and acquire aggressive features. Within this laboratory, the “Cytoskeleton and Cancer Progression” research group, led by Dr. Clément Thomas, focuses in particular on the actin cytoskeleton and related signaling pathways in the context of breast cancer.


Confocal microscopy image. Accumulation of actin filaments (in green) at the immunological synapse of a resistant cancer cell in contact with an NK cell (in red). Cell nuclei are shown in blue.

LIH

The actin cytoskeleton is essential for maintaining the shape of cells and enabling motility, and plays critical roles in tumor cell invasion and metastasis. Until now it remained unclear whether the cytoskeleton also contributes to immune evasion, rendering cancer cells resistant to attacks by the immune system.

Actin mounts up in resistant tumor cells

Cancer cells are able to develop resistance to immune attack by escaping from NK-mediated cell death. Tumor immune escape is a major hurdle limiting the efficacy of current immunotherapies. In the present research work, Dr. Antoun Al Absi, Dr. Thomas and co-workers investigated whether the actin cytoskeleton plays a role in immune evasion. ‘When NK cells or cytotoxic T cells get in contact with target cells, a so-called immunological synapse is formed’, explains Dr. Thomas.

‘This contact interface allows NK cells to focus and release cytotoxic granules toward the target cells leading to their killing. It is well known that rearrangement of the cytoskeleton inside NK cells is necessary for the formation of the immunological synapse and granule release to the target cells.

However, the organization of actin filaments in target cells remains poorly explored. This gave us impulse to investigate what happens with the cytoskeleton of cancer cells in contact with NK cells.’

The scientists thus took a closer look at possible alterations of the actin cytoskeleton in breast cancer cells comparing NK-mediated cytotoxicity resistant and susceptible cell lines. They revealed that all the cell lines they investigated contain two subpopulations: one showing a very prominent accumulation of actin filaments at the level of the immunological synapse, and one with no such accumulation.

‘When using high-throughput imaging flow cytometry we observed that actin massively concentrates at the immunological synapse in tumor cells resistant to NK cytotoxicity, indicating a causal link between this actin response and resistance,’ states Dr. Al Absi who conducted the major part of the experimental work.

Actin(g) as a protection

To be sure that the actin response is truly associated to the resistance phenotype, the researchers conducted experiments in which genes were silenced to impair actin polymerization. This abolished the actin response and made previously resistant cancer cells remarkably more susceptible to NK cell attack. Thus the actin response is linked to the protection of cancer cells against the attack of NK cells.

The team next analyzed the effects of the actin rearrangement in cancer cells at the molecular level. ‘We observed a difference in the density of ligands on the surface of cancer cells’. On cells with an actin response, a significant increase in immune-inhibitory ligands such as HLA-A, -B, -C and the immune checkpoint protein PD-L1 was found at the contact site with NK cells.

On top of that, we detected that a lower amount of the cytotoxic protein granzyme B reaches the resistant target cell,’ explains Dr. Al Absi. The researchers thus concluded that the actin response protects cancer cells from lysis by limiting the accumulation of granzyme B. They are currently evaluating the hypothesis that the actin response actually drives the local recruitment of immune-inhibitory ligands to alter the cytotoxic function of immune cells.

Finally, to validate their results, Dr. Al Absi and co-workers also monitored the actin response using primary NK cells isolated from donors to exclude that the phenomenon is solely observable with the NK cell line initially used for the study. Indeed, the actin response and its protective effects were also observed in this context.

The present research work revealed a new fascinating mechanism by which cancer cells escape from the immune response and may pave the way for new cancer treatment options. ‘The actin response that drives breast cancer cell resistance to NK-cell mediated cell lysis presents an interesting therapeutic target,’ stresses Dr. Thomas.

‘We now need to investigate the molecular pathways that underlie the actin response and search for components that could be directly targeted by drugs. We hope that we will find a way to sensitize resistant cancer cells to NK cell-mediated cytotoxicity as this would considerably improve the efficacy of NK cell-based immunotherapy. Moreover, we are now evaluating the possibility that the actin response also provides resistance against cytotoxic T cells.’

Research funding and collaborations

This research work is a major part of the PhD thesis of Dr. Antoun Al Absi who graduated in July 2018 and was supported by an AFR PhD grant from Luxembourg National Research Fund (FNR). The research team is supported by further research grants from the FNR, F.R.S.-FNRS Télévie and the Luxembourg Cancer Foundation “Fondation Cancer”.

The project was mainly carried out at the Laboratory of Experimental Cancer Research at LIH’s Department of Oncology under the lead of Dr. Clément Thomas and included a collaboration with the National Cytometry Platform at LIH’s Department of Infection and Immunity and the INSERM unit “Immunologie Intégrative des Tumeurs” at the Gustave Roussy Institute in Villejuif, France.

Wissenschaftliche Ansprechpartner:

Dr. Clément Thomas - Principal Investigator
Cytoskeleton and Cancer Progression research group
Laboratory of Experimental Cancer Research
Department of Oncology
Luxembourg Institute of Health
E-mail: clement.thomas@lih.lu

Originalpublikation:

http://cancerres.aacrjournals.org/content/early/2018/08/08/0008-5472.CAN-18-0441...

Dr Malou Fraiture | idw - Informationsdienst Wissenschaft

More articles from Life Sciences:

nachricht How to construct a protein factory
19.09.2019 | Universität Bern

nachricht Quality Control in Cells
19.09.2019 | Universität Heidelberg

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Stevens team closes in on 'holy grail' of room temperature quantum computing chips

Photons interact on chip-based system with unprecedented efficiency

To process information, photons must interact. However, these tiny packets of light want nothing to do with each other, each passing by without altering the...

Im Focus: Happy hour for time-resolved crystallography

Researchers from the Department of Atomically Resolved Dynamics of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg, the University of Hamburg and the European Molecular Biology Laboratory (EMBL) outstation in the city have developed a new method to watch biomolecules at work. This method dramatically simplifies starting enzymatic reactions by mixing a cocktail of small amounts of liquids with protein crystals. Determination of the protein structures at different times after mixing can be assembled into a time-lapse sequence that shows the molecular foundations of biology.

The functions of biomolecules are determined by their motions and structural changes. Yet it is a formidable challenge to understand these dynamic motions.

Im Focus: Modular OLED light strips

At the International Symposium on Automotive Lighting 2019 (ISAL) in Darmstadt from September 23 to 25, 2019, the Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP, a provider of research and development services in the field of organic electronics, will present OLED light strips of any length with additional functionalities for the first time at booth no. 37.

Almost everyone is familiar with light strips for interior design. LED strips are available by the metre in DIY stores around the corner and are just as often...

Im Focus: Tomorrow´s coolants of choice

Scientists assess the potential of magnetic-cooling materials

Later during this century, around 2060, a paradigm shift in global energy consumption is expected: we will spend more energy for cooling than for heating....

Im Focus: The working of a molecular string phone

Researchers from the Department of Atomically Resolved Dynamics of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg, the University of Potsdam (both in Germany) and the University of Toronto (Canada) have pieced together a detailed time-lapse movie revealing all the major steps during the catalytic cycle of an enzyme. Surprisingly, the communication between the protein units is accomplished via a water-network akin to a string telephone. This communication is aligned with a ‘breathing’ motion, that is the expansion and contraction of the protein.

This time-lapse sequence of structures reveals dynamic motions as a fundamental element in the molecular foundations of biology.

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Optical Technologies: International Symposium „Future Optics“ in Hannover

19.09.2019 | Event News

Society 5.0: putting humans at the heart of digitalisation

10.09.2019 | Event News

Interspeech 2019 conference: Alexa and Siri in Graz

04.09.2019 | Event News

 
Latest News

DGIST achieves the highest efficiency of flexible CZTSSe thin-film solar cell

19.09.2019 | Power and Electrical Engineering

NTU Singapore scientists develop technique to observe radiation damage over femtoseconds

19.09.2019 | Physics and Astronomy

Optical Technologies: International Symposium „Future Optics“ in Hannover

19.09.2019 | Event News

VideoLinks
Science & Research
Overview of more VideoLinks >>>