Postdoc: Single-molecule microscopy of checkpoint therapeutic action on T cells

Work Activities

Checkpoint blockage focuses on targeting inhibitory immune receptors with antibodies to prevent their activation by blocking ligand binding. This strategy has revolutionised immunotherapy helping millions of cancer patients with some spectacular results, providing a novel path to potentiate immune responses against tumour cells. Nevertheless, most patients fail to benefit from these antibody-based therapies highlighting critical pitfalls of the current checkpoint blockade approach: one of them is that blocking receptor-ligand interactions is insufficient to shut down inhibitory signalling completely. 

By taking up this postdoc position, you will help changing the current ligand-centric “blockade” paradigm and focus on developing molecules that induce dephosphorylation of immune receptors (so-called RIPR molecules) to shut down their signalling entirely, in contrast to currently available therapeutics. Our approach termed REPRESSIT (Regulated phosphatase recruitment ends sustained signaling of inhibitory targets) can completely shut down even tonic inhibitory receptor signaling (Fernandes, R.A. et al. Immune receptor inhibition through enforced phosphatase recruitment. Nature 586, 779–784 (2020)). But how do this phosphase-recruiting molecule need to be designed to optimally shut down signalling?

In close collaboration with the Fernandes group (University of Oxford) and our other REPRESSIT partners, you will analyse the spatiotemporal dynamics of how different designs of RIPR molecules (Receptor Inhibition by Phosphatase Recruitment) modulate T cell receptor signalling both in live cells and model lipid bilayers with reconstituted receptor domains, using single-molecule fluorescence microscopy and single-particle tracking techniques. You will study both receptor organisation and receptor signalling (adaptor protein recruitment). From these experiments, we will understand the molecular basis of RIPR function and determine general biophysical design principles to further improve the potency of RIPR molecules. The performance of promising new RIPR designs we find will then be tested and compared against conventional antibodies preclinical models by our REPRESSIT partners. Ultimately, this project aims at developing and establishing proof-of-concept of the REPRESSIT platform for bringing these molecules to the clinic and patients.

Qualifications

You need to meet the requirements for a doctors-degree (PhD) and must have research experience in a non-Dutch academic environment. We are looking for a (bio)physicist who has already worked with single-molecule fluorescence techniques or an experimental (bio)chemist with strong experience in biophysical techniques and data analysis. Experience with single-molecule fluorescence microscopy or super-resolution microscopy, automated data analysis and coding (Python) is highly desired; knowledge of cell culture and/or protein biochemistry and/or model lipid systems would be an advantage. You should like the idea of working in a collaborative, ambitious and international environment. We ideally look for a candidate who can start this position in March 2025.

Work environment

AMOLF is part of NWO-I and initiate and performs leading fundamental research on the physics of complex forms of matter, and to create new functional materials, in partnership with academia and industry. The institute is located at Amsterdam Science Park and currently employs about 140 researchers and 80 support employees. www.amolf.nl.

Our group – We are a supportive and social research group of about 8 PhD students and postdocs, which work together in small teams on various projects from immunological signalling to signalling in synthetic cells. The collaborative and social atmosphere includes to the other research groups at the AMOLF institute at the Science Park in Amsterdam East. Our group has been making recent technical advances, including a new single-molecule tracking method based on DNA-PAINT that we recently developed (Nat Commun 2021, Nat Commun 2023), new in vitro assays (ACS Syn Biol 2021, ACS Omega 2024), and imaging approaches developed by our lab and others (JACS 2013, Nat Immun 2016, PNAS 2019), all to closely investigate the intricate molecular details of cellular signaling.

https://amolf.nl/research-groups/physics-of-cellular-interactions

Working conditions

• The working atmosphere at the institute is largely determined by young, enthusiastic, mostly foreign employees. Communication is informal and runs through short lines of communication.
• The position is intended as full-time (40 hours / week, 12 months / year) appointment in the service of the Netherlands Foundation of Scientific Research Institutes (NWO-I) for the duration of 2 years.
• Salary is in scale 10 (CAO-OI) which starts at 4.065 Euro’s gross per month, and a range of employment benefits.
• AMOLF assists any new foreign Postdoc with housing and visa applications and compensates their transport costs and furnishing expenses.

More information?

For further information about the position, please contact Kristina Ganzinger: k.ganzinger@amolf.nl or Raquel Martinez Gonzalez: R.MartinezGonzalez@amolf.nl.

Application

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Online screening may be part of the selection.

Diversity code

AMOLF is highly committed to an inclusive and diverse work environment: we want to develop talent and creativity by bringing together people from different backgrounds and cultures. We recruit and select on the basis of competencies and talents. We strongly encourage anyone with the right qualifications to apply for the vacancy, regardless of age, gender, origin, sexual orientation or physical ability.

AMOLF has won the NNV Diversity Award 2022, which is awarded every two years by the Netherlands Physical Society for demonstrating the most successful implementation of equality, diversity and inclusion (EDI).

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