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Creation of a three dimensional (3D) scene to unravel Cytotoxic T cell Resistant mechanisms (CRiMe) in non-small cell lung cancer.
Belgium (BeMSA) - Vrije Universiteit Brussel VUB, Brussels
Laboratory for Molecular and Cellular Therapy, Department of Biomedical Sciences
Dr. Cleo Goyvaerts
Dr. Cleo Goyvaerts
Type of Research Project
- Basic science
What is the background of the project?
Non-small cell lung cancer remains the leading cause of cancer-related deaths worldwide. Despite magnificent breakthroughs in antitumor immunotherapy, the majority of patients currently do not show any durable benefit. As immunotherapy aims to stimulate the cancer-killing potential of cytotoxic T lymphocytes (CTLs), these clinical findings suggest that there is an urgent need to decipher other yet unidentified CTL-killing resistant mechanisms (CRMs) that are currently hampering immunotherapy efficacy. Previous studies have linked CRMs to cancer cells as well as to the physical and immunosuppressive hindrance installed by their surrounding stromal cells. These make cancer cell specific CTL-mediated killing and installment of CRMs a very dynamic process, for which proper CRM screening assays are lacking.
What is the aim of the project?
This project aspires to develop an innovative human three dimensional (3D) CTL-killing resistant mechanisms (CRM) screening assay that enables
1) the induction of novel cancer cell intrinsic CRMs,
2) the evaluation of the impact of stromal cells on the induction of cancer-cell intrinsic CRMs, and
3) the validation of the impact of the identified CRMs.
The knowledge that will be gained from this project will foster a more scientifically based clinical development of novel drugs and combinations that could be delivered together with current immunotherapies. In addition, this knowledge can provide valid biomarkers for patient selection prior to administration of expensive and toxic immunotherapy combinations.
What techniques and methods are used?
- Cell culture and generation of three dimensional (3D) lung tumor spheroids with hanging-drop culture technique
- Evaluation of dynamic killing process via flow cytometry, IncuCyte® live cell imaging, confocal microscopy, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA) on supernatant and quantitative polymerase chain reaction (qPCR)
- Possibly also generation of, and applications with lentiviral vectors encoding clustered regularly interspaced short palindromic repeats/CRISPR-associated 9 (CRISPR/Cas9) for the creation of gene-specific knock out lines
What is the role of the student?
- The tasks of the student will be performed on his/her own
- The tasks will be done under supervision
What are the tasks expected to be accomplished by the student?
- Thaw and freeze cell lines
- Keep different cell lines in culture by expanding them every 2-3 days
- Isolate cluster of differentiation 11b+ (CD11b+) myeloid cells from human whole blood samples
- Generate three dimensional (3D) spheroids
- Follow staining procedures and analysis for flow cytometry
- Follow evaluation via IncuCyte® and confocal microscopy
- Generate lentiviral vectors encoding clustered regularly interspaced short palindromic repeats/CRISPR-associated 9 (CRISPR/Cas9) to knock out selected genes (corresponding to selected CTL-killing resistant mechanisms (CRM))
Will there be any theoretical teaching provided (preliminary readings, lectures, courses, seminars etc)
- The student will be informed about the general lab rules on the day of arrival <br> - In addition, literature will be provided to help the student understand the rationale of the project and procedures performed <br>
What is expected from the student at the end of the research exchange? What will be the general outcome of the student?
- The student will prepare a scientific report - The student’s name will be mentioned in a future publication
What skills are required of the student? Is there any special knowledge or a certain level of studies needed?
- Ability to work in a team
- Work according to the good laboratory practice (GLP)
- Handle cell cultures in a sterile way
Subjects passed: basic knowledge on immunology would be convenient
Previous experience with: cell cultures
Are there any legal limitations in the student’s involvement
Type of students accepted
This project accepts: - Medical students - Graduated students (less than 6 months) - Pre-Medical students from the American-British system - Students in biomedical fields
- Trujillo JA; Sweis RF; Bao R; Luke JJ. T cell-inflamed versus Non-T cell-inflamed tumors: a conceptual framework for cancer immunotherapy drug development and combination therapy selection. Cancer Immunol Res. 2018;6:990–1000.
- Ameratunga M; Chénard‐Poirier M; Moreno Candilejo I et al Neutrophil‐lymphocyte ratio dynamics of patients with advanced solid tumours on phase I trials of PD‐1/PD‐L1 inhibitors. Eur J Cancer 2018; 89: 56–63.
- Nath S; Devi GR. Three-dimensional culture systems in cancer research: focus on tumor spheroid model. Pharmacol Ther. (2016) 163:94–108. 10.1016/j.pharmthera.2016.03.013
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