(2lz) Spatial Systems Biology for Translational Cancer Immunotherapy

I am an instructor at Cedars Sinai Medical Center pursuing a faculty position in Chemical Engineering. My overarching research goal as an independent scientist is to improve immunotherapy by studying and engineering the tumor microenvironment. I believe the key to cancer immunotherapy lies in the spatial biology of the tumor, and my research lab will study the architecture of tumor tissue and spatial biomarkers of patient response, develop new computational methods to demystify immune cell spatial biology, and create methods to perturb and study immune cells in tumors. My teaching goal is to demonstrate how translational cancer research embraces complexity and systems biology to achieve clinical results, with the assistance of materials and nanotechnology. These goals are the product of my research journey, where I have integrated materials science, systems biology, and now clinical translational science into my research vision. I will present vignettes for my major projects and publications, and I will summarize how these projects shape my independent research vision and my preliminary data and funding results to achieve these goals.

Research Interests:

My research program will consist of three primary aims. The first aim is to analyze the spatial biology of tumor tissue using computational techniques that I developed. For three years I have been studying tumor spatial biology at Cedars Sinai Medical Center using highly multiplexed spatial protein analysis, with first and co-first authored studies on Hodgkin’s Lymphoma (under review at Nature Communications), colorectal cancer metastases (in press at Cell Metabolism), and ovarian cancer (under revision at PNAS). I will discuss the pipelines created to identify spatial and protein biomarkers to predict patient outcomes, paying close attention to spatial features such as specific ligand-receptor interactions driving immune-tumor aggregation, and localized immune subtypes in tumor vs stromal regions of tissue. To pursue these aims further, I am the PI of an R01 submitted in June 2023, focused on integrating localized spatial signaling features in a cohort of >400 patients with Hodgkin’s Lymphoma, where immune cells form so-called “rosettes” around tumor cells with potential competing tumor-promoting and tumor-suppressing signaling. I was also awarded an NCATS KL2, Tower Cancer Research Foundation Career Development Award, and Grace O Foundation Award Grant for related projects on tumor spatial biology.

The second aim is to study the role of T cells in tumor immunology by studying antigen-specificity using computational and modeling approaches. First, I will briefly describe 4 linked studies where T-cell receptor sequencing was used to study the patient response to vaccination against COVID-19 at population levels using human samples collected at the hospital. Next, I developed a computational strategy that effectively compares T-cell receptors to discover sequence motifs that predict antigen-specificity. Using a computational model based off of the binding-restrictive orientation of the TCR-MHC complex, I consider the sequences of antigen-specific TCRs of all lengths, and perform entropic analysis to identify “essential” and “super-essential” 2-mers, consecutive amino acids needed for antigen recognition. The study, in press at Cell Systems, also considers patterns of 2-mer usage across antigens, and validates computational findings using protein folding simulations with Alphafold. I will propose to use T cell informatics to highlight the clonal spatial heterogeneity of tumor tissue. I am the site PI of a P30 award in collaboration with Yuri Fedoriw at UNC to study the T cell repertoire heterogeneity in hematological cancer.

The third aim of my research program will be to develop materials-based assays to analyze and perturb spatial biology. I previously developed tools for single cell analysis and intracellular delivery to study aspects of cancer and immune heterogeneity. I will briefly describe how these techniques (microfluidics, high-aspect ratio nanowire penetration into cells, high-avidity T-cell receptor pulldown) will be adapted to study immune cell perturbations in cancer models of immunotherapy. My primary focus is to create a nanoparticle-based platform to study immune cell perturbations in therapeutic T cells such as Chimeric Antigen Receptor T cells (CAR-T). As Perturb-seq is able to test libraries of genetic perturbations using sequencing data, I am proposing a platform to test libraries of molecular perturbations using spatial imaging data.

Teaching Interests:

My primary teaching interest is to drive greater recognition of spatial biology in biomedical engineering and sciences, and to communicate how spatial biology draws from different areas of engineering. This includes method development via materials and chemistries, computational tools for big data and image processing, systems biology for interpreting spatial data, and finally device and cellular engineering used to translate spatial insights into clinical settings. I recently organized a 2-day spatial biology symposium at our hospital, which was attended by over 300 people and featured speakers from across the greater Los Angeles area. I also organize a bi-weekly spatial biology seminar series and a weekly workshop on imaging data analysis. Our hospital does not have regular coursework or teaching opportunities, so I have been involved in a new initiative called Translational Research in Bioengineering, where I serve as a steering committee member focused on raising awareness of bioengineering techniques in the hospital. I believe that I have a unique teaching perspective, as for the last 5 years I have been positioned at either a small research institute or at a research hospital. An alternative teaching goal of mine is also to de-silo engineering departments by highlighting collaborative opportunities with medical and translational researchers. To this end, I participate in the yearly Cedars-Sinai Caltech Collaboration Symposium, which was the basis for a Merkin Translational Seed Grant Award and a submitted R21, which will be resubmitted soon.

Candidate Background:

I am an NCATS KL2 fellow and instructor at Cedars Sinai Medical Center, where I am also the Associate Director of the Spatial Molecular Profiling Core Facility. I study the spatial biology of tumors and T-cell receptor informatics, previously under the mentorship of Dr. Akil Merchant. Before Cedars-Sinai, I was an F32 Postdoctoral Fellow at the Institute for Systems Biology and Caltech in the lab of Dr. James Heath. I obtained my PhD in Materials Science and Engineering with Dr. Nicholas Melosh at Stanford University, where I was an NSF GRFP and NDSEG fellow.