The Steinhart Lab

The Steinhart Lab aims to decode how tumors suppress T cell function and leverage these insights to design new immunotherapies for treatment-resistant cancers, with an emphasis on Head and Neck Cancer. By combining CRISPR-based functional genomics with primary human models, including patient-derived TILs and tumor organoids, we seek to identify the tumor signals and genetic programs that drive T cell dysfunction and reveal actionable pathways to restore durable antitumor immunity.

Immunosuppressive tumor microenvironments suppress T cell functions leading to ineffective antitumor immune responses. In some patients this can be overcome with immunotherapies such as checkpoint blockade or TIL therapy, however in many cases these therapies fail. We are investigating what signals and genetic programs cause TIL dysfunction and how we can restore their function through genetic engineering and druggable targets.

In the UCSF Department of Otolaryngology Head and Neck Surgery, we have excellent access to primary human tumor tissue from Head and Neck Cancer. We are leveraging these resources to study the functional genomics of primary human TILs and associated tumor and other immune cells to make discoveries in the most translationally-relevant settings.

Dysfunctional immune cells must overcome a multitude of immunosuppressive signals in the tumor microenvironment to mount an effective antitumor response. Understanding how these signals integrate and what their redundancies are will be critical for discovering synergistic therapeutic combinations to improve immunotherapy efficacy and response rates. We have developed CRISPR interference and activation tools that are exceptional for introducing multiplexed perturbations to immune cells to rapidly and systematically uncover genetic interactions that improve our understanding of the genetic wiring of cells, and nominate synergistic targets for therapeutic combination strategies. 

Systematic functional genetic technologies such as high-throughput CRISPR screens and single-cell technologies have provided unprecedented genetic perturbation and measurements capabilities in human cells, accelerating our understanding of human diseases. We aim to push the boundaries of functional genomic technologies to capture complex genetic interactions, cell-cell communication, and temporal dynamics at the highest resolution to push the boundaries of our discovery engine for immuno-oncology research.