MATCHMAKERS: Solving TCR Recognition and Design Via Integrated High-Throughput Screening, Structural, Functional, and Computational Approaches


Michael Birnbaum, PhD, Massachusetts Institute of Technology


David Baker, PhD
University of Washington, USA

Regina Barzilay, PhD
Massachusetts Institute of Technology, USA

Brandon DeKosky, PhD
Massachusetts Institute of Technology, USA

Peter Bruno, PhD
University of California San Francisco, USA

Dirk Busch, MD, PhD
Technische Universität München, Germany

Stephen Elledge, PhD
Brigham and Women’s Hospital, USA

Christopher Garcia, PhD
Stanford University, USA

Johanna Olweus, MD, PhD
University of Oslo, Norway

Sergio Quezada, PhD
University College London, United Kingdom

Ton Schumacher, PhD
Netherlands Cancer Institute, The Netherlands

Nikolaos Sgourakis, PhD
Children’s Hospital of Philadelphia, USA

T cells are the vigilant sentinels of the immune system, continuously monitoring the body and identifying infected, mutated, or otherwise aberrant cells. Throughout cancer evolution, a dynamic interplay unfolds between tumor cells and surveilling T cells. Mature tumors employ various strategies to evade T cell surveillance, and the aim of many immunotherapies is to restore susceptibility to T cell activity. Immunotherapies have revolutionized oncology by reinvigorating existing tumor-reactive T cells via immune checkpoint blockade, stimulating new T cell responses through therapeutic vaccines, bolstering tumor infiltrating lymphocytes, or re-targeting T cells via CAR-T cell technology or bispecific engagers. Despite these breakthroughs, a substantial proportion of patients exhibit resistance to immunotherapy, underscoring the imperative to develop more powerful and precise therapies.

T cells continually sample the intracellular milieu of somatic cells via their T cell receptors (TCR). Each T cell possesses a unique TCR enabling it to monitor short peptides presented on major histocompatibility complexes (MHC) across all nucleated cells. Typically, these peptides represent “self” proteins indicative of normal cellular function and go unnoticed by TCRs. However, in instances of infection, mutation, or cancer-associated protein expression, “non-self” peptides are presented, prompting TCR recognition and subsequent T cell-mediated elimination of the afflicted cell. A pressing challenge is predicting the array of peptide-MHC (pMHC) complexes recognized by a given TCR. Despite the clinical relevance of TCR–pMHC interactions, translating current experimental methods for pMHC identification into broadly applicable clinical approaches remains elusive. By the same token, for TCR-based therapies, no reliable technology has been developed to design receptors that will be potent against a specific target without inadvertently targeting healthy tissues.

The MATCHMAKERS team will embark on an ambitious research program to revolutionize TCR-pMHC pair prediction. Central to their approach is the integration of sequence and structure datasets, leveraging the group’s unique experience to merge these approaches into a unified pipeline. The team will curate new sequence and structure datasets scaled for advanced machine learning algorithms, develop novel experimental methods for data acquisition, and devise computational strategies addressing the nuances of TCR-pMHC binding and structure. The international and interdisciplinary group of investigators will combine data collected from natural TCR repertoires, datasets generated through molecular engineering strategies, structural and biochemical analysis, and the latest advances in artificial intelligence-based predictions and machine learning.

Computational prediction and design of TCR-pMHC pairs stands to revolutionize cancer immunotherapy and broaden the patient base benefiting from T cell-directed treatments. The MHC subtypes that are currently the best-studied and therefore the most tractable to prediction algorithms may not effectively target a significant portion of cancer patients because of the extensive polymorphism of MHCs across populations. The MATCHMAKERS project seeks to expand patient diversity for T cell response assessment, particularly focusing on MHC subtypes with limited data, which tend to be more prevalent in low- and middle-income countries. Therapeutically, while T cell-based therapies against hematological malignancies have successfully found targetable cell surface proteins, solid tumors have yielded few useful shared antigens, and peptide-MHC complexes seen by TCRs remain a critical gateway to effective immunotherapy of solid tumors. Ultimately, this work has the potential to impact every cancer currently treated or undergoing immunotherapy development, including melanoma, lung cancer, renal cell cancer, and breast cancer, even those previously unresponsive to treatment efforts.

MATCHMAKERS is the third Cancer Grand Challenges team supported by The Mark Foundation, bringing the organization’s investment to over $30 million. In 2022, the Foundation co-funded the NexTGen team, led by Professor Catherine Bollard (Children’s National Hospital, US) and Dr. Martin Pule (University College London, UK), to develop novel immunotherapies for childhood solid tumors. In 2019, The Mark Foundation co-funded the SPECIFICANCER team, led by Professor Stephen Elledge (Harvard Medical School and Brigham and Women’s Hospital), to develop a deeper understanding of why cancers grow in some tissues but not in others and to find new ways to prevent or treat cancers in these tissues. The Mark Foundation is committed to advancing global cancer research and driving progress in tackling cancer’s most complex challenges. These large-scale, international Cancer Grand Challenges team initiatives are exemplary of the type of interdisciplinary research The Mark Foundation prioritizes supporting.