Yu Leo Lei, D.D.S., Ph.D.

Associate Professor of Dentistry,
Dept. of Periodontics and Oral Medicine
Associate Professor of Otolaryngology-
Head and Neck Surgery
U-M Rogel Cancer Center
Accepting Students?


Dr. Lei is a tenured Associate Professor at the University of Michigan Ann Arbor. He received his PhD at the Lineberger Comprehensive Cancer Center, the University of North Carolina at Chapel Hill. He completed his residency and a T32-supported fellowship in Head and Neck Oncology at the University of Pittsburgh Hillman Cancer Center. He is a pathologist-immunologist who actively provides service to many institutional, foundational, and national committees, such as the Rogel Cancer Center research committee, steering committee of the NCI Cancer Moonshot Immuno-Oncology Translational Network, and the NCI PREVENT panel. His group pioneers the identification of oncogenic and viral inhibitors of the innate immune system. He is a recipient of the NIH Rising Stars award. His basic and translational immunoprevention program focuses on the regulation of Pattern Recognition Receptors-mediated innate immune sensing of cancers, with an eye towards the engineering approaches to normalize innate immune sensors. His collaborative work is highly cited and published in well-respected journals such as the Journal of Clinical Investigation, Immunity, Clinical Cancer Research, Nature Immunology, Cell, Nature, Science, among others. 

Research Interests

Pattern Recognition Receptors (PPRs) constitute the first line of defense against “non-self” antigens, which are encountered during microbial infections and cancer development. With the characterization of new PRR families, such as Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs) and cGAS-STING-mediated cytoplasmic DNA-sensing molecules, novel regulatory mechanisms of PRR signaling are rapidly emerging as main cancer immune escape mechanisms. We pioneered in the identification of novel PRR regulators. Our laboratory has developed a unique collection of toolkits in the following areas.

**Mechanisms Regulating Cancer Immune Escape** Emerging evidence suggests that PRR not only detect molecular structures associated with pathogens but those linked to cellular and tissue damage. Due to increased genome instability in cancer cells and chemoradiation therapy, PRR-mediated sensing of cytoplasmic DNA, a classic danger signal for cellular damage, triggers the production of chemokines that recruit immune cells to the tumor bed. But this process is frequently suppressed by squamous cell carcinomas, leading to immune escape. We are among the first to show that oncogenic signaling in squamous cell carcinomas suppresses PRRs as a key mechanism driving T-cell exclusion.

**Immune Engineering Strategies to Sensitize Cold Cancer to Immune Checkpoint Blockade** Cold cancers are featured by insufficient elicitation of tumor-specific T-cell immunity. In order to expand the tumor-specific CD8+ T-cell repertoire, our group utilizes advanced nanotechnologies to deliver and optimize the intra-lesional immune microenvironment. For example, we have shown that our nano-vaccines can sensitize cold tumors to immunotherapy, and a combination of nano-vaccines with checkpoint blockade leads to significantly expanded tumor-specific effector T cells, reduced T-cell exhaustion and better tumor control.

**Immunogenomics Approaches to Identify Cold Cancer** With the emerging combinatorial strategies for cold cancer, precise identification of this group of tumors is essential for the selection of optimal treatment protocols. In collaboration with a computational geneticist, we have developed a robust and novel immune-cell deconvolution machine learning tool, FARDEEP, to map the landscape of tumor-infiltrating lymphocytes. In addition, we have optimized a single-cell RNA-Seq-informed immune profiling pipeline to examine lineage segregation and immune subsets differentiation trajectories.

Research Opportunities for Rotating Students

We have recently NIH funded projects that we hope to recruit students to:

Project 1: We are interested in understanding the metabolic requirements for innate immune activation.

Project 2: We are interested in learning how driver oncogenes in transforming epithelial cells establish a tolerogenic niche and promote immune escape as a function of time.

Project 3: We are interested in learning the role of gut microbiome in regulating cancer immunogenicity.