Kai W. Wucherpfennig is a German-American scientist known for his research in T cell immunology, with an emphasis on cancer immunology and autoimmunity. He is a professor in the Department of Immunology at Harvard Medical School and the Department of Neurology at Brigham & Women’s Hospital. At Dana-Farber Cancer Institute (DFCI), he serves as the chair of the Department of Cancer Immunology and Virology and as Co-director of the Parker Institute for Cancer Immunotherapy. He is the Nancy Lurie Marks Professor of Neurology in the Field of Medical Oncology at Harvard Medical School. He is also a co-founder of several biotech companies that have advanced his discoveries into clinical trials.
Education
Wucherpfennig earned an MD and PhD degree from the University of Göttingen in Germany. He then conducted postdoctoral research at Brigham’s & Women’s Hospital, Harvard Medical School with Drs. David Hafler and Howard Weiner (T cell biology of multiple sclerosis), followed by postdoctoral work at Harvard College with Dr. Jack Strominger (biochemistry of autoimmunity-associated MHC proteins).
Research Career
Cancer Immunotherapy
Wucherpfennig’s current research focuses on T cell-mediated cancer immunity, ranging from discovery of novel immune mechanisms to the development of new therapeutic strategies and their clinical translation. An emphasis on resistance mechanisms to immunotherapy has led to discovery of a series of novel therapeutic strategies.
CARM1 epigenetic enzyme. The Wucherpfennig lab developed an in vivo strategy for the discovery of therapeutic targets for cancer immunotherapy. The activation and proliferation of T cells is strongly inhibited in tumors, and this genetic screening approach identifies those edited T cells that become enriched in tumors because a critical negative regulator has been inactivated by RNAi or CRISPR/Cas9 . In vivo screening of an epigenetic library led to the discovery of the CARM1 enzyme: inactivation of the gene in T cells greatly increases their infiltration into tumors and their anti-tumor activity . Importantly, CARM1 is relevant in all three major cell populations of the cancer immunity cycle, including dendritic cells, T cells and cancer cells. Inactivation of CARM1 in dendritic cells greatly increases their ability to activate tumor-specific T cells, while inactivation of CARM1 in cancer cells sensitizes them to T cell-mediated attack . His lab is now collaborating with chemistry colleagues to develop a CARM1 inhibitor that can be advanced to a phase 1 clinical trial. The discovery of CARM1 highlights an important principle of his work: his lab focuses on the discovery of therapeutic opportunities that result in a cooperative response by multiple immune cell populations based on the hypothesis that such synergy is critical for protective anti-tumor immunity.
MICA – NKG2D pathway. DNA damage induces the expression of the stress proteins MICA and MICB (MICA/B) by human cancer cells that activate the NKG2D receptor on NK cells and T cells. However, cancer cells evade this immune recognition pathway through proteolytic shedding of MICA/B. The Wucherpfennig lab discovered that this immune evasion mechanism can be targeted with mAbs directed at the MICA/B α3 domain, the site of proteolytic shedding. These MICA/B mAbs substantially increase the density of these immunostimulatory ligands on cancer cells and induce NK cell-mediated immunity against metastatic disease . His lab also developed a cancer vaccine targeting the MICA/B α3 domain. This vaccine induces a coordinated T cell and NK cell response, resulting in efficacy even against cancer cells that have lost MHC class I expression and are therefore resistant to T cell-mediated cytotoxicity . In collaboration with Fate Therapeutics, his lab developed CAR T cells and NK cells that target MICA/B, and these cellular therapies yield substantial anti-tumor activity against diverse human cancer types in NSG mouse models . These discoveries have been translated into clinical.
CD161 – CLEC2D pathway. Single cell analysis of T cells in human glioblastoma demonstrated that the inhibitory CD161 receptor is highly upregulated by T cells in these tumors compared to blood T cells. The CD161 receptor strongly inhibits the cytotoxicity of CD8 T cells following binding to the CLEC2D ligand which is expressed by cancer cells and macrophages in GBM . In collaboration with Dane Wittrup at MIT, his lab developed fully human monoclonal antibodies that block the CD161 – CLEC2D interaction. These antibodies substantially increase the activity of human T cells against cancer cells . Based on these discoveries, Wucherpfennig co-founded Immunitas Therapeutics together with Mario Suva, Dane Wittrup and Aviv Regev.
Human cancer immunity. A major goal of the lab is to discover key principles of immune organization in human cancer, with the goal of developing therapeutic strategies based on these insights. The lab therefore performs mechanistically oriented studies in the context of clinical trials that evaluate novel therapeutic strategies. In collaboration with Nino Chiocca, the lab performed an in-depth spatial analysis of T cell-mediated immunity in glioblastoma patients treated with a novel oncolytic virus . Even though glioblastoma is poorly infiltrated by T cells prior to this intervention, deep and persistent T cell infiltration is present even at late timepoints (>1 to 2 years) following treatment. In situ analysis also provides evidence for ongoing T cell-mediated cytotoxicity, and this spatial parameter correlates with clinical outcomes.
The lab also examines the molecular mechanisms of immune-related adverse events in cancer patients treated with immune checkpoint blockade, with a specific focus on colitis, a common and frequently severe side effect. Activated CD8 T cells with a strong cytotoxicity profile are enriched in these colitis lesions, and molecular tracing using the T cell receptor as a cellular barcode shows that the majority of these colitis-associated T cells originate from tissue-resident T cells in the gut . These results thus indicate that immune related adverse events can result from reactivation of tissue-resident T cells at barrier organs . A separate study analyzed T cell responses in patients with head and neck cancer treated with pre-surgical immune checkpoint blockade . T cells with a tissue residency program emerged as a major early T cell population that expand within tumors, suggesting that T cells with a tissue residency program are relevant to both the efficacy and toxicity of immune checkpoint blockade.
Autoimmune diseases
Autoimmune diseases are initiated by self-reactive T cells, explaining why the MHC gene locus is strongly associated with susceptibility to many human autoimmune diseases. The Wucherpfennig lab investigated the molecular mechanisms of T cell recognition of self-antigens in autoimmune diseases, with a focus on multiple sclerosis (MS) and type 1 diabetes (T1D). He defined the structural requirements for self-peptide binding by human MHC proteins and T cell recognition of these self-peptide/MHC complexes . This work led to the important discovery that human myelin-specific T cells can be activated by viral peptides that meet the structural requirements for MHC binding and TCR recognition. This work provided the first experimental evidence for TCR cross-reactivity and molecular mimicry in a human autoimmune disease, and many other labs have extended this discovery to other autoimmune diseases .
The Wucherpfennig lab also determined the crystal structure of the MS-associated HLA-DR15 protein, in collaboration with Don Wiley. This structure identified unique features of the peptide binding groove that explain the binding of specific myelin peptides . His lab also determined the first crystal structure of an autoimmune T cell receptor (TCR) – peptide-MHC complex. This autoimmune TCR – isolated from a MS patient - bound with an unusual topology to the HLA-DR15 - myelin peptide complex, potentially explaining how this autoimmune TCR escaped negative selection in the thymus . Transgenic mice that expressed this human TCR and HLA-DR15 developed spontaneous CNS autoimmunity, documenting the biological relevance of this myelin-specific TCR .
An important feature of human autoimmune T cells is that they bind with rather low affinity to their pMHC ligand. This low TCR affinity affects the formation of immunological synapses formed by such human self-reactive T cells. Autoimmune synapses contained many signaling TCR microclusters but did not form organized TCR and LFA-1 adhesion zones. These unusual IS features may facilitate escape from negative selection by self-reactive T cells encountering very small amounts of self-antigen in the thymus. However, these same features may enable acquisition of effector functions by self-reactive T cells encountering large amounts of self-antigen in the target organ of the autoimmune disease .
Basic principles of antigen recognition by T cells
The Wucherpfennig lab also discovered key principles of T cell antigen recognition. They discovered the organizing principle of the TCR – CD3 complex. A striking feature of the TCR-CD3 complex is the presence of nine highly conserved, potentially charged residues in the transmembrane helices. Using a novel method for the isolation of intact radiolabeled protein complexes, the lab demonstrated that one basic and two acidic transmembrane residues were required for the assembly of the TCR with each of the three signaling dimers (CD3δε, CD3γε and ζ-ζ). This remarkable three-helix arrangement applied to all three assembly steps and represented the organizing principle for the formation of this intricate receptor structure . In collaboration with James Chou, the lab then determined the NMR structure of the ζ-ζ transmembrane dimer. The two aspartic acids that interact with an arginine residue of the TCRα chain created a single structural unit at the ζ-ζ dimer interface . The lab then extended this discovery to all activating immune receptors that assemble with a signaling dimer: in each case, a positively charged amino acid (lysine or arginine) interacted with a pair of acid residues of the signaling dimer, creating a three-helix interface. This spatial organization arose by convergent evolution in multiple independent receptor families .
One of the major questions in T cell biology is how ligand binding results in TCR activation. The lab discovered that the cytoplasmic domains of CD3 signaling subunits dynamically interact with the inner leaflet of the plasma membrane. The NMR structure of the lipid-bound state of the CD3ε cytoplasmic domain revealed deep insertion of the two key tyrosines into the hydrophobic core of the lipid bilayer. Receptor ligation thus needs to result in unbinding of the CD3ε ITAM from the membrane to render these tyrosines accessible to Src-family kinases. Sequestration of key tyrosines into the lipid bilayer represents a mechanism for control of receptor activation . The lab then demonstrated that a similar mechanism applies to the cytoplasmic domain of the CD28 co-stimulatory receptor that is required for full T cell activation . High-resolution imaging studies demonstrated that early TCR signaling results in changes in lipid composition of clustered TCRs, resulting in release of the cytoplasmic domain from the membrane .