Brian Baker

Research Interests

Research in the Baker lab is directed at the biochemical and biophysical underpinnings of molecular recognition, emphasizing cellular immunity and its role in infection and disease, autoimmunity, cancer, and transplantation. We are primarily interested in antigen presentation by major histocompatibility complex molecules, their recognition by T cell receptors, and the design and engineering of novel therapeutics based on T cell-mediated immunity. Our approach integrates structural biology, protein biophysics, computational biochemistry, molecular immunology, and a growing amount of machine learning and artificial intelligence.

Most cells in the body express class I or class II major histocompatibility complex proteins, or MHC proteins, which bind and “present” peptides derived from intracellular or extracellular proteins. Recognition of a peptide/MHC complex by a T cell receptor (TCR) on the surface of a helper or cytotoxic T cell stimulates a T cell-mediated immune response. While best recognized for its role in the immune response to viruses, T cell mediated immunity also plays a key role in the immune response to other pathogens, in cancer, autoimmunity, and transplant rejection.

Many projects in the lab are centered on the structural, biophysical, and immunological principles of TCR recognition of peptide/MHC complexes. The TCR-pMHC interaction is one of the most complex protein-ligand interactions known to biology. We aim to understand the complexities from a physical perspective, relying heavily on structural biology and experimental and computational biochemistry, but also an increasing amount of data science and in vitro and in vivo immunology. Our overall aims are to understand how TCR recognition influences immunity in health and disease.

As we gain insight into TCR recognition of peptide/MHC, we are using this knowledge to engineer TCRs with improved recognition properties with the goal of developing novel therapeutics. Other projects are centered on understanding how recognition is communicated across the cell membrane. Here, we aim to gain a deeper understanding of the physical changes that occur upon binding and how these influence protein architecture, motion, and connections with cell signaling units. The influence of applied forces on protein complexes in the immune system is a new and exciting area of emphasis.

We have a special interest in the immune response to cancer. There is a close connection between cellular immunity and cancer, and in a very short time, immunotherapy has emerged as a fourth “pillar” of cancer therapy. We study the development of exciting, new personalized vaccines for cancer as well as sophisticated approaches that involve the creation of genetically engineered immune systems for cancer patients. In these areas, we leverage our understanding of the structural and biophysical underpinnings of TCR recognition of peptide/MHC to help drive advances in cancer immunology. A new focus on the lab is the T cell immunology of transplant rejection, and how we can leverage our understanding to better predict, monitor, and control outcomes in transplantation.

Our lab is highly collaborative, and we work with a range of chemists, biologists, and clinicians, including academic and industry teams engaged in a variety of clinical trials, ranging from cancer vaccines, to the latest cell therapies, to novel means to control the rejection of transplanted organs.

Selected Publications

• Shi, T.; Burg, A. R.; Caldwell, J. T.; Roskin, K. M.; Castro-Rojas, C. M.; Chukwuma, P. C.; Gray, G. I.; Foote, S. G.; Alonso, J. A.; Cuda, C. M.; Allman, D. A.; Rush, J. S.; Regnier, C. H.; Wieczorek, G.; Alloway, R. R.; Shields, A. R.; Baker, B. M.; Woodle, E. S. and Hildeman, D. A. "Single Cell Transcriptomic Analysis of Renal Allograft Rejection Reveals Insights into Intragraft TCR Clonality" 2023 The Journal of Clinical Investigation, e170191. DOI: 10.1172/JCI170191.
• Singh, N. K.; Alonso, J. A.; Devlin, J. R.; Keller, G. L. J.; Gray, G. I.; Chiranjivi, A. K.; Foote, S. G.; Landau, L. M.; Arbuiso, A. G.; Weiss, L. I.; Rosenberg, A. M.; Hellman, L. M.; Nishimura, M. I. and Baker, B. M. "A Class-Mismatched TCR Bypasses MHC Restriction Via an Unorthodox but Fully Functional Binding Geometry" 2022 Nature Communications, 13 (1), pp.7189-0. DOI: 10.1038/s41467-022-34896-0.
• Rosales, T. J. and Baker, B. M. "Chaperoning the Dance of Antigen Presentation" 2022 Nature Chemical Biology, 18 (8), pp.796-797. DOI: 10.1038/s41589-022-01069-5.
• Liu, C.; Liu, H.; Dasgupta, M.; Hellman, L. M.; Zhang, X.; Qu, K.; Xue, H.; Wang, Y.; Fan, F.; Chang, Q.; Yu, D.; Ge, L.; Zhang, Y.; Cui, Z.; Zhang, P.; Heller, B.; Zhang, H.; Shi, B.; Baker, B. M. and Liu, C. "Validation and Promise of a TCR Mimic Antibody for Cancer Immunotherapy of Hepatocellular Carcinoma" 2022 Scientific Reports, 12 (1), pp.12068-5. DOI: 10.1038/s41598-022-15946-5.
• Ayres, C. M. and Baker, B. M. "Peptide-Dependent Tuning of Major Histocompatibility Complex Motional Properties and the Consequences for Cellular Immunity" 2022 Current Opinion in Immunology, 76, 102184. DOI: 10.1016/j.coi.2022.102184.
• Chandran, S. S.; Ma, J. Q.; Klatt, M. G.; Dundar, F.; Bandlamudi, C.; Razavi, P.; Wen, H. Y.; Weigelt, B.; Zumbo, P.; Fu, S. N.; Banks, L. B.; Yi, F.; Vercher, E.; Etxeberria, I.; Bestman, W. D.; Paula, A. D.; Aricescu, I. S.; Drilon, A.; Betel, D.; Scheinberg, D. A.; Baker, B. M. and Klebanoff, C. A. "Immunogenicity and Therapeutic Targeting of a Public Neoantigen Derived from Mutated PIK3CA" 2022 Nature Medicine, 28 (5), pp.946. DOI: 10.1038/s41591-022-01786-3.

>> See our full list of publications at PubMed >>