Using Single-cell and Spatial Multi-omics to Improve Adoptive Cell Therapy against Pancreatic Cancer

Project Summary/Abstract Adoptive T cell therapy (ACT) has been effective against certain blood cancers but has had limited success against solid tumors, such as pancreatic cancers, largely because ACT T cells become dysfunctional within the tumor-microenvironment (TME). There is a big knowledge gap on the causes of dysfunction in ACT T cells, mainly because there are so many T-cell-intrinsic regulators and T-cell-extrinsic TME suppressive factors that can all potentially contribute to ACT T cell dysfunction. With the ultimate, goal of overcoming T cell dysfunction and improving therapeutic efficacy, I seek a more comprehensive understanding of how ACT T cells are molecularly programmed by intrinsic epigenetic regulators to become dysfunctional, and how extrinsic TME factors further suppress the function of ACT T cells using ACT-treated mouse models and data from ACT-treated pancreatic cancer patients. Specifically, using single-cell multi-omics (including epigenomics) and spatial omics, along with the computational analysis and functional experiments, I aim to: 1) Identify targetable T cell-intrinsic epigenetic regulator(s) of ACT T cell dysfunction in TME, 2) Identify targetable intra-TME cellular & molecular interactions that suppress ACT T cell function. My previous wet-lab & dry-lab training, and my extensive experience with the single-cell analysis of both cancer and the immune cells, make me well-suited for the project. The project can significantly clarify the fundamental biology of T cell dysfunction and reveal actionable clinical strategies for improving ACT efficacy. The proposed computational frameworks should also be broadly applicable to a wide spectrum of contexts. The benchmark datasets should also serve as a rich, resource to the broad field of cancer immunotherapy for hypothesis generation and testing. My long-term goal is to lead an independent research group at a top research university, using systems biology to study quantitative questions in immuno-oncology, especially ACT against solid tumors. Over the course of this award, I will be supported by primary mentor, Dr. Philip Greenberg, a pioneer of ACT therapy for cancer, with a remarkable track record in science and mentoring. My co-mentors, Drs. Henikoff, Newell, Gottardo, Setty, Chapuis, are all renowned experts of epigenomics, single-cell and spatial omics, computational biology and clinical science, respectively, providing complementary training for my independence transition. They will all assist me in navigating the transition to an independent faculty position. Work will be conducted at Fred Hutch Cancer Center, which offers all the state-of-the art facilities required for the successful of the Aims in addition to a collegial scientific & training environment, and strong institutional support.