Department of Chemistry and Biochemistry
Harper Cancer Research Institute
University of Notre Dame

Our Research

Overview

Research in the Baker lab is directed at understanding and manipulating molecular recognition in the cellular immune system.
Venn Diagram - PlainWe are primarily interested in antigen presentation by major histocompatibility complex molecules, their recognition by T cell receptors, and the design and engineering of novel cancer therapeutics based on T cell-mediated immunity. Our approach integrates structural biology, protein biophysics, and molecular immunology.

Most cells in the body express class I or class II major histocompatibility complex proteins (MHC), or MHC proteins, which bind and “present” peptides derived from intracellular or extracepMHCllular 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 transplant rejection, autoimmunity, and cancer.

Many projects in the lab are centered on the structural and biophysical principles of TCR recognition of peptide/MHC. 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, using techniques such as protein crystallography, NMR, mass spectrometry, and experimental and computational biophysics, all supported by a range of cellular and immunological experiments. 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 molecular changes that occur upon binding and how these influence protein architecture, motion, and connections with cell signaling units.

Lastly, we have a special interest in the immune response to cancer. There is a close connection between cellular immunity and cancer, and some of the earliest cancer treatments of the modern era focused on eliciting or enhancing anti-cancer immune responses (the Cancer Research Institute has an excellent primer on cancer and the immune system). We study the development and enhancement of cancer vaccines 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 in order to help drive advance in cancer immunology.

Current projects:

1. T cell receptor dynamics, cross-reactivity, and specificity.  Molecular motion in TCRs can influence immune recognition, yet the extent and impact is poorly understood. Further, manipulation of molecular motion is a potential strategy for engineering TCRs with improved or novel recognition functions. We are using a variety of computational and experimental approaches to investigate and manipulate TCR motion.

2. Distribution of binding energy in TCR-pMHC interfaces.  TCRs recognize peptide antigens only in the context of MHC proteins. Although contacts are made to both peptides and the MHC, the immune response is normally peptide-centric. How is binding energy distributed in these interfaces, and what is the role of stochastic structural variation vs. evolution in shaping this distribution? Can it be manipulated as a means to engineer improved receptors? We are using structural, bioinformatic, and biophysical approaches to address these questions.

3. Development of generalizable TCR design algorithms.  With our collaborators at the University of Massachusetts, we are using our knowledge of TCR structures, physical properties, and binding properties to develop approaches that permit the structure-based computational design of receptors with desired recognition properties. This project integrates structural biology, biophysics, computational design, and molecular immunology.

4. Peptide-dependent tuning of MHC flexibility. We and others have shown that different peptides can impact the flexibility of MHC proteins in a functionally important way. We are using computational and experimental approaches to ascertain the extent and overall immunological significance of this phenomenon.

5. Development of personalized cancer vaccines. With our collaborators at the University of Connecticut, we are evaluating neo-antigens present in cancers for use as individualized, patient-specific cancer vaccines. This project leverages our expertise in peptide-MHC interactions with computational assessments of peptide-MHC structural and conformational stability.

6. Development of novel receptors for immunotherapy of hepatitis C associated liver cancer. With our collaborators at Loyola University, we are using our expertise in TCR structure-based design to develop receptors that drive the rejection of hepatitis C associated liver cancer.