As a chemical engineer with extensive training in systems biology, cancer biology, immunology, and adoptive T cell therapy (ACT), my research aims to overcome key barriers limiting the success of engineered T cells as living therapeutics for solid tumors. While ACT has transformed the treatment landscape for hematologic malignancies, its efficacy against solid tumors remains constrained by two major challenges: (1) the heterogeneous differentiation of T cells during ex vivo manufacturing, which results in variable functional potency and durability, and (2) the suppressive tumor microenvironment (TME), which disrupts T cell function through immunosuppressive signaling, metabolic stress, and spatial constraints. My research program seeks to address these fundamental limitations by integrating high-dimensional (single-cell and spatial multi-omics with lineage tracing) and high-throughput perturbation (CRISPR-based screens, Perturb-seq) technologies to systematically dissect and engineer the temporal and spatial dynamics of T cell fate and function, including (1) strategically designing the manufacturing process to steer T cells toward favorable fates with optimal anti-tumor potential, and (2) empowering these living therapies with novel “superpowers” to withstand the suppressive “forces” of the tumor microenvironment.
Research Accomplishments
Having acquired extensive training in cancer biology, immunology, adoptive T cell therapy, computational and systems biology, with experience in relevant high-dimensional and high-throughput technologies (single-cell- and spatial- omics, temporal CRISPR-activation/inhibition screens and perturb-seq, etc.), and with having already resolved some aspects of both proposed challenges, I believe I am uniquely positioned to lead my proposed research program.
Graduate: Working with Drs. James Heath and David Baltimore at Caltech, and in collaboration with Dr. Antoni Ribas at UCLA, my Ph.D. studies utilized computational and systems biology approaches to investigate the fundamental plasticity and heterogeneous nature of cancer cells (Su et al PNAS 2017; Su et al PLoS Comput. Biol. 2019; Su et al Nat. Commun. 2020; Du* and Su* et al Nat. Commun. 2020) and how this leads to tumor resistance to traditional chemo/targeted-therapy drugs. These deep dives into the complexity of cancer sparked my interest in harnessing the immune system as a “living drug” that can chase cancer, a “moving target”.
Postdoc: The beginning of my Damon Runyon-supported postdoc in Quantitative Biology coincided with the pandemic lockdown, which provided me an opportunity to not only receive extensive immunology training from world-leading scientists collaborating on my projects such as Drs. Leroy Hood, Mark Davis, Lewis Lanier, Jeff Bluestone, Phil Greenberg, etc., but also utilize my systems biology expertise to address this health problem and investigate how the immune system controls or fails to control COVID-19 infections. Through comprehensive multi-omic analyses of heterogeneous immune systems across hundreds of patients over their disease trajectories (Su, et al Cell 2020 and Cell 2022), I was able to consolidate millions of data points into a single coordinated immune-response module that independently tracks with various critical clinical metrics (e.g. severity, mortality). My computational immunology approaches are proving to be broadly applicable for understanding immune responses in other contexts.
Together with an MD-PhD student in the Greenberg lab, I also developed a computational framework that can infer the metabolic activities of immune cells from single-cell RNA-seq (Lee* and Su* et al Nat. Biotech. 2022). I subsequently utilized this framework to improve the cell generation process to yield better “quality” ACT T cell products, addressing a crucial issue in current ACT strategies. Analyzing nearly a half million T cells from >300 patients revealed dysfunctional CD8 T cells downregulated mannose metabolism. This discovery inspired an advanced manufacturing workflow incorporating mannose supplementation to modify operative metabolic pathways, which significantly improved the ability of T cells to control tumors in several in vivo tumor models, including with human T cells (Qiu* and Su* et al Cancer Cell 2024). These findings establish mannose as a pivotal regulator of T cell fate and demonstrate that T cell states can be metabolically pre-programmed during ex vivo generation to enhance their fitness for therapeutic applications.
In parallel, I applied the computational framework I developed for deconvoluting large-scale immune datasets (Su et al Cell 2022) onto atlases of T cell dysfunction and identified an E3-ligase that controls two critical arms of T cell dysfunction in the TME: T cell exhaustion and metabolic stress. Perturbing the E3-ligase in T cells significantly improved the efficacy of ACT across various in vivo models (Cheng* and Su* et al under revision). These findings underscore the importance of proteostasis, a previously underexplored area in immunotherapy research, and highlight metabolic stress and mitochondrial health as a substantive barrier that, in concert with T cell exhaustion—contributing to T cell dysfunction in the TME.
Additionally, I have been leading a project analyzing ACT T cells recovered from the TME of pancreatic cancer (PDA) patients enrolled in a first-in-human trial of pancreatic cancer TCR T cell therapy in synergy with a parallel clinically relevant ACT mouse model (KPC) for PDA. This project is funded in part by my K99/R00 grant. Integrating single-cell multi-omics, CRISPR-screens, and spatial transcriptomes, we found a unique dominant dysfunctional phenotype acquired by ACT T cells that reside in a specific spatial niche in the TME, and I am now testing strategies to overcome this phenotype to enhance efficacy. (Su et al, in preparation).
Teaching Interests
My comprehensive chemical engineering education throughout my undergraduate and graduate degrees, has equipped me to teach any chemical engineering classes. As a teaching assistant for multiple courses in Caltech’s Chemical Engineering Department, I gained experience in instructing core subjects such as kinetics, transport, and thermodynamics, as well as interdisciplinary topics in systems biology and biomolecular engineering. Additionally, my research has provided me with expertise in molecular and cellular biology, genetics, cancer biology, immunology, and bioinformatics. My strong quantitative background as a chemical engineer has been instrumental in uncovering the engineering principles underlying biological systems, and I am eager to bring this perspective into the classroom. I am enthusiastic about mentoring the next generation of engineers and scientists by integrating rigorous engineering principles with cutting-edge biological research.
Selected Publications
(from 34 total, including 11 first/co-first, 7 co-senior/co-corresponding)
*Denotes co-first author
Selected Awards, Fellowships, and Grants (16 Of 32 Total)