Projects

Cancer Immunology

Timing the T Cell Response to Cancer

Understanding when and how the immune system first recognizes and responds to tumors is crucial for improving cancer immunotherapy. The adaptive immune system plays a vital role in tumor surveillance, but the timing of immune engagement with tumors remains unclear. This project aims to determine the timing of the adaptive immune response to cancer using phylogenomic tree construction. We will perform single-cell whole genome sequencing of tumor-infiltrating lymphocytes (TILs) in liver and kidney cancers to provide estimates of when TIL expansions occur relative to tumor development, identifying windows for therapeutic intervention. These insights could lead to earlier and more targeted immunotherapy strategies, improving patient outcomes​.

Chronic Inflammation and Immune Remodeling in Liver Cancer

Chronic inflammation is a known risk factor for cancer, and understanding its impact on immune remodeling is key to cancer prevention and treatment. Hepatocellular carcinoma (HCC) often arises from inflammatory premalignancies like metabolic dysfunction-associated steatotic liver disease (MASLD), making it an ideal model for studying the transition from inflammation to cancer. This project investigates the origins and phenotypic changes of T cell expansions from inflammatory premalignancies to HCC. We will conduct multiomic analysis of T cell somatic evolution using single-cell RNA sequencing and whole genome sequencing in HCC and MASLD biopsies. The project will identify T cell expansions originating in premalignant tissues and characterize the phenotypic changes associated with compromised immunosurveillance. Understanding these dynamics could lead to new strategies for cancer prevention and treatments targeting specific immune deficiencies in HCC​.

T Cell Dynamics in Response to Immunotherapy

Determining how immunotherapies affect T cell clonotypes is essential for enhancing their efficacy and predicting patient responses. Immunotherapies, particularly immune checkpoint inhibitors, have revolutionized cancer treatment, yet their mechanisms of action and the factors influencing patient responses are not fully understood. This project examines the clonotype and phenotype dynamics of T cells during immunotherapy in metastatic kidney cancer. We will use single-cell multiomic analysis to trace the evolution of T cell clonotypes and their phenotypic changes throughout immunotherapy treatment. The project will reveal whether immunotherapies rescue pre-existing T cell clones or recruit new ones and identify associated transcriptional changes. These findings could help predict patient responses to immunotherapy and inform personalized treatment strategies​.

Immune Aging and Dysfunction

Somatic Evolution of T Cell Immunosenescence and Aging

Understanding the mechanisms of immune aging is crucial for developing interventions to maintain immune function in the elderly. Memory CD8+ T cells undergo significant age-related changes, including reduced diversity, increased clone size and changes in phenotype, which contribute to immune dysfunction and increased disease susceptibility in the elderly. This research will employ single-cell multiomics to explore the genomic and transcriptomic correlates of inflammatory and immunosenescent phenotypes in elderly individuals and to elucidate how immune dysfunction evolves with age.