Unravelling the immune system's antigen proofreading process

Nik and his lab set out to tackle a complex problem: how major histocompatibility complex class I (MHC-I) molecules select high-quality peptides from millions of cellular options to present to T cells. Using advanced structural biology techniques such as cryo-electron microscopy (CryoEM) and nuclear magnetic resonance (NMR) spectroscopy, the lab captured a previously elusive structural intermediate involving the molecular chaperone TAP binding protein-related (TAPBPR). This discovery unveiled a dynamic proofreading mechanism ensuring that only the most stable antigens are selected for immune presentation.

The ability of MHC molecules to bind and present the right peptides is fundamental to adaptive immunity. Our findings deepen our understanding of how the immune system streamlines its responses to pathogens and cancer. 

Dr Nik Sgourakis

One of the study’s key contributions lies in its translational potential. The insights gained could help improve the accuracy of computational methods for predicting antigens and developing targeted cancer therapies.

The lab discovered that the chaperone TAPBPR can efficiently exchange peptides on MHC proteins directly in human cells and help to upregulate MHCI expression. “By leveraging these findings, we aim to enhance the immunogenicity of cold tumours, offering new therapeutic avenues,” explains Nik. The lab is already exploring applications in other paediatric cancers, including neuroblastoma, in collaboration with John Maris, another member of the NexTGen team. 

This research challenges previously held beliefs about antigen selection. The study resolves a long-standing controversy in the field by debunking the "scoop loop" model of TAPBPR-mediated proofreading, instead proposing a mechanism of dynamic allostery. “This represents a paradigm shift in how we understand the selection of peptide antigens,” says Nik.

The lab’s innovative approach allows for rapid in-vitro validation of potential antigens, eliminating the need for labour-intensive experiments. These findings hold promise for advancing cancer vaccines and immunotherapies.

Nik reflects, “We've been working on the system for the past ten years, and it's been a series of incremental discoveries and improvements that allowed us to elucidate this mechanism, which has been sort of a holy grail in this field.”

This study exemplifies the power of fundamental research in driving medical innovation. By unravelling the complexities of antigen proofreading, team NexTGen has not only advanced our understanding of adaptive immunity but also laid the groundwork for breakthroughs in cancer treatment. As Nik emphasises, “This is just the beginning of what these findings can achieve.” 

Nik credits the success of this work to interdisciplinary collaboration enabled by Cancer Grand Challenges. “We’ve developed a shared language and framework, allowing us to synergise effectively,” he says. The team’s engagement with patient advocates has also been transformative. Nik reflects, “Their focus on immediacy has driven us to prioritise translational opportunities that could directly benefit patients.”

Nik has learnt from the collaborative opportunities presented by being part of both NexTGen and MATCHMAKERS teams (which is tackling the T-cell receptors challenge). “There are a lot of ways we can leverage the technologies that have been developed within MATCHMAKERS to further enable and drive projects in the NexTGen team”

The lab is already carving out new projects based on these findings. Beyond cancer immunotherapy, they aim to refine computational tools for predicting antigen immunogenicity and develop reagents to enhance T-cell targeting. A follow-up study focusing on cold tumours is expected soon, underscoring the team's commitment to translating basic science into clinical impact. 

Nik has built a career around a passion for understanding proteins at the cellular level. His journey began under the mentorship of two renowned scientists: Chemistry Nobel Prize winner David Baker in Seattle (who is also part of team MATCHMAKERS), where he focused on protein modelling and design, and with Adriaan Bax at the NIH, where he explored biophysics and molecular immunology. These experiences laid the foundation for his independent research program. Over the past decade, Nik has shifted his focus toward translational science, driving projects with real-world impact.

Nik’s approach exemplifies the power of mentorship in advancing both science and the next generation of researchers. “Throught my career, I consider myself really lucky, both through the participation in NexTGen and MATCHMAKERS, but also through the really amazing scientists that I had the opportunity to interact with, some of whom are currently in my lab. The main driving force for me, is to be the best resource and mentor to my lab.”