Background
B.S., Molecular Biology, Brigham Young University (2000)
Ph.D., Cancer Biology, Stanford University School of Medicine (2006)
Post-doctoral Fellow, Tumor Biology & Angiogenesis, Genentech, Inc. (2006–2007)
Post-doctoral Scholar, Neurology, UC San Francisco (2007–2011)
Scientist/Senior Scientist, Neuroscience, Genentech, Inc. (2011–2020)
Cancer Research
- TREM2 signaling and regulation: TREM2 (triggering receptor expressed in myeloid cells 2) expression in tumor-associated macrophages (TAMs) has the effect of suppressing the activity of cytotoxic T cells toward tumor cells. In mouse models, anti-PD-1 tumor immunotherapy is more potent when Trem2 is deleted or when a TREM2-blocking antibody is co-administered (Cell 182:886-900; Cell Reports 37:109844). The cellular processes by which TREM2 signaling in TAMs results in suppression of cytotoxic T cell activity toward tumor cells have not been defined, and modulation of TREM2 signaling by other receptors has not been reported. We are studying the mechanisms of TREM2 signaling in myeloid cells by expressing TREM2 tagged with SBP-TEV-EGFP (streptavidin-binding peptide, TEV protease site, and enhanced green fluorescent protein) that can be used to study both subcellular localization through GFP fluorescence and protein–protein interactions through tandem affinity purification. We are also studying whether GPCRs (G protein-coupled receptors) can modulate TREM2 signaling in a reporter cell system.
- Immune checkpoint proteins (PILRA, CD33, and PD-1): We are also studying whether immune checkpoint proteins—receptors that contain ITIMs (immunoreceptor tyrosine-based inhibitory motifs)—can suppress TREM2 activity. Like TREM2, PILRA and CD33 are expressed by myeloid cells. Whereas TREM2 is an activating receptor, PILRA and CD33 are inhibitory receptors. Therefore, promoting PILRA or CD33 activity could suppress TREM2 signaling in TAMs and thereby help promote cytotoxic T cell activity toward tumor cells. We currently have a grant from BrightFocus Foundation ($300K over 3 years, motivated by the associations of TREM2, PILRA, and CD33 with the risk of Alzheimer’s disease) to study whether PILRA and CD33 can suppress TREM2 signaling. In addition to studying PILRA and CD33, we are also testing whether the checkpoint protein PD-1 can suppress TREM2 signaling. PD-1 is well-known for its expression in T cells and its role in suppressing cytotoxic T cell activity toward tumor cells. However, PD-1 is also expressed in TAMs, where it could potentially suppress TREM2. Therefore, PD-1-blocking antibodies intended to de-repress cytotoxic T cell function could also block PD-1 in TAMs and have the counterproductive effect of promoting TREM2 signaling and TAM-mediated suppression of cytotoxic T cell activity. Understanding which checkpoint proteins can inhibit TREM2 in myeloid cells will provide mechanistic insights for how TAMs regulate tumor immunology and will inform our therapeutic approaches for modulating TAM biology.
- PTK2B: The tyrosine kinase PTK2B (a.k.a. Pyk2) has been implicated in tumor cell metastasis (J Clin Med 11:2130), tamoxifen resistance (Mol Cell Proteomics 14:2887) and TAM infiltration (J Exp Clin Cancer Res 40:304). PTK2B is a homolog of FAK (focal adhesion kinase) but has received much less research attention. Motivated in part by the association of PTK2B with Alzheimer’s risk, we are identifying novel PTK2B-interacting proteins and investigating whether PTK2B is a downstream effector of TREM2 signaling in myeloid cells. Discovering PTK2B-interacting proteins and signaling mechanisms will help reveal mechanisms of cell motility involved in TAM infiltration and tumor metastasis.