Tackling one of immunology’s greatest questions
Future Leaders Spotlight: Meet MATCHMAKERS with Benoit Nicolet
MATCHMAKERS are taking on our T-cell receptor challenge. Here, future leader Benoit Nicolet takes us through how the team is tackling the challenge, emphasising the scale of the problem, and what it is like to be a part of this scientific dream team and receive emails from one of the newest Nobel Prize winners.
Future Leaders are early career researchers (postdocs, PhD students, junior group leaders, assistant professors and other roles) and key members of our funded teams and global community, making significant contributions to tackling their teams' challenge.
About Benoit
I am Benoit Nicolet, Postdoc in the lab of Ton Schumacher at the Dutch Cancer Institute (NKI) in Amsterdam, Netherlands. I never could have imagined being where I am now. After deciding that Architecture/Building engineering wasn’t for me, I took on the challenge to start biology at university with zero biology/chemistry in the prior four years. I then moved to Glasgow (Scotland) to study Microbiology (and learn English, being a Frenchman). Loved it. But what was happening on the human side of infections (a.k.a. immunology)? I moved to Amsterdam for an MSc in Immunology and went on to do a PhD in Immunology in the lab of Monika Wolkers at Sanquin, Amsterdam, to understand how T cells regulate their killing capacity. Now I am putting all my dry and wet lab skills to help solve one of immunology’s greatest questions.
The problem
Our cells constantly acquire mutations. Most mutations are repaired, but many persist and accumulate overtime, contributing to the development of cancerous cells. These mutations in tumours are a signature in that they differ from ‘healthy’ cells that have lower mutation counts. This very difference between tumour and healthy tissues allows for a therapeutic window and recognition by the immune system. Some mutations will be shared between cancers, but most are patient-specific. This limits off-the-shelf approaches and requires personalised therapies. Over the last ~25 years, the immune system and especially T cells have been shown to be critical in controlling tumour growth. T cells are very skilled at specifically targeting tumour cells by recognizing mutated proteins with their T-cell receptors (TCRs).
Cracking the TCR code
Team MATCHMAKERS aims to decode the language of TCRs to design novel TCRs directed against mutated proteins in tumours. This would be a game-changer in cancer therapies!
TCRs recognize foreign peptides presented by large protein complexes on the Major Histocompatibility Complex (MHC). To crack the code of the TCR-peptide-MHC (TCR-pMHC) complex we need masses of paired information. The problem is there are ~1015 possible TCR combinations and ~1012 possible protein peptides, presented by ~104 different MHC molecules. Oh, and to make the system even more complex, TCRs are expected to sometimes cross-react with different peptides. We can’t search at random, as there are more TCR-pMHC combinations than stars in the universe (~1031 possible combinations, 1024 observed stars). Our team has developed smart ways to screen for TCR-pMHC pairs which will yield thousands of pairs that can then be analysed with advanced AI to understand the code for TCR-pMHC recognition. We expect that with our data combined with advances in structural and language-based AI models (think AlphaFold- and ChatGPT-like models), we will be able to generate new TCRs that recognize tumour mutated peptides within years. I think one of the coolest parts of this project is that we can learn from our designs (and mistakes): we iteratively learn from nature, then design novel TCRs that can recognize tumours, test these TCRs in the lab, learn what works, then loop back and repeat, in order to find new TCR-pMHC pairs. It is unbelievably motivating to help solve the TCR-pMHC code problem, one of immunology’s greatest questions.
Our amazing team
Of course, complex problems means that a lot of great scientists need to come together. Cancer Grand Challenges’ support has allowed something beautiful: all the labs I followed for years are now teammates through MATCHMAKERS. I find this super inspiring. Even crazier, I now receive emails which include the new Nobel Prize winner David Baker (needless to say that these emails are framed in my living room). In addition, to make sure that our great team is still anchored in a reality that will benefit patients, we have the honour to work with talented and ultra-dedicated patient advocates. Personally, I find this incredibly rewarding to be given the means to do cool science, surrounded by inspiring people, with an amazingly ambitious goal that will bring about new powerful cancer treatments.
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Through Cancer Grand Challenges, team MATCHMAKERS is funded by Cancer Research UK, the National Cancer Institute and The Mark Foundation for Cancer Research.