Overview:
By integrating innovative CRISPR-based genetic screening approaches with patient-derived humanized models, we aim to elucidate novel therapeutic strategies that bestow engineered cell therapies the ability to provide long term cures for patients. We have a particular focus on employing locoregional or “surgically” delivered cell-based therapies against genitourinary cancers, with the goal of developing minimally invasive, organ sparing, curative treatments for these patients. Our work resides within the intersection of surgery, engineering, immunology and genetics, providing a highly collaborative, stimulating and multidisciplinary ecosystem to conduct research within.
Theme 1: Overcoming the solid tumor microenvironment
The solid tumor microenvironment of genitourinary cancers are characterized by profound immune suppression with the accumulation of cytokines, regulatory cells and harsh physiochemical properties that pose significant barriers for successful immunotherapy. Our group is focused on identifying strategies to circumvent these barriers through an integrative genomics approach coupling multi-dimensional immune profiling of surgical samples with high-content spatial CRISPR screens. The goal of this work is to identify targets within the tumor microenvironment that can be exploited to improve engineered cell therapy.
Theme 2: Mapping the genetic architecture of inflammatory cell death
The induction of an inflammatory cell death response capable of priming protective antitumor immunity following cancer therapy is highly desirable and likely necessary to impart long term durable remissions. However, the genetic circuits that wire cancer cells towards an inflammatory (e.g. pyroptosis, necroptosis) vs. sterile cell death (e.g. apoptosis) response remains poorly understood given the significant cross-talk, redundancy and pleiotropy inherent in cell death signaling pathways. To address this fundamental knowledge gap our group is systematically mapping how genes interact to promote inflammatory cell death using high-content spatial and single cell CRISPR screens. We also study the subsequent immune response following inflammatory cell death initiation to understand how these intrinsic genetic interactions can be exploited to improve long term generation of protective immunity following cellular immunotherapy.
Theme 3: Developing novel humanized model systems
A major barrier to identifying mechanisms of response and resistance to cellular immunotherapy is the lack of experimental models required for their discovery and interrogation. Our group is exploring the utility of patient derived organoid and humanized murine models for capturing the genetic and immunological heterogeneity that is pervasive amongst genitourinary cancers.
