Over 20,000 allogeneic hematopoietic stem cell transplants (allo-HSCT) are conducted annually worldwide, confirming its effectiveness as a treatment for patients with otherwise lethal malignancies. Allo-HSCT is beneficial for treatment of malignancies because of the graft-versus-tumor effects (GVT) by allogeneic CD8+ T cells contained within the HSCT inoculum. Although an effective treatment, allogeneic CD8+ T cells also cause graft-versus-host disease (GVHD), which causes significant morbidity and mortality in ~30-70% of transplant recipients. Thus, the separation of GVHD from GVT effects is necessary to improve allo-HSCT outcomes. The goal of this proposal is to devise new strategies to separate GVT from GVHD after allo-HSCT. I have been investigating the impact of manipulating TCR signal transduction pathways in allo-HCST settings. We provide robust and reproducible evidence that T cells harboring a YF mutation at Y145 of the adaptor molecule SLP-76 (Y145F) don't develop GVHD, while preserving the anti-tumor effect in a mouse model of major mismatch allo-HCST. Further, we provide evidence that protection against GVHD is mediated T cell- intrinsically by the Y145F KI TCR signaling defect in addition to the expression of Eomesdermin (Eomes), necessary for the T cells to carry out optimal GVT effects.
Our Specific Aims i nclude (1) the investigation of the mechanisms by which ITK inhibition alleviates GVHD and (2) to delineate the role of Eomes for CD8+ T cells to mount GVT responses. We will accomplish these Aims by using mouse models of allo-HSCT combined with a variety of genetically manipulated mice (ITK KO, Eomes KO, etc.) and pharmacological interventions (ITK inhibitor, Wnt agonists). We will use a variety of techniques including qPCR, flow cytometry, Western blotting as well as unbiased approaches such as RNA-seq and microarray analysis. Although much research has been performed in the area of allo-HSCT, there is still a need for new therapeutic strategies to separate GVHD from GVT. Our proposal will fill in this gap by investigating how ITK inhibition in conjunction with Eomes expression by CD8+ T cells can attenuate GVHD while preserving GVT effects. Through my training, I have acquired the skills to investigate T cell activation in a variety of allo-HSCT models and to biochemically and molecularly assess the mechanisms of T cell activation. Together with expert collaborators including Drs. Taku Kambayashi (expert in GVHD), Martha Jordan (expert in T cell signaling), Jan Burkhardt (expert in cell biology and migration), and Warren Pear (expert in transcription factors), the Aims of the proposal are likely to be successfully accomplished. My immediate career goal is to obtain a faculty position at an academic institution and to successfully compete for an R01 proposal. My long-term career goal as I establish myself into an independent scientific investigator is to uncover decisive regulators of the immune system responsible for cancer progression, and seek for novel therapeutic targets for cancer treatment as part of the fight against hematological malignancies.
Allogeneic hematopoietic stem cell transplantation is a potentially curative therapy for many types of cancer, but is often associated with alloreactive T cell-mediated graft-versus-host disease (GVHD) that can cause significant morbidity and mortality. Thus, there is an imminent need for strategies to enhance anti- tumor immunity without GVHD. The objective of this application is to investigate strategies for promoting anti- tumor immunity without GVHD and their underlying mechanisms, which will have profound implications for cancer prevention and therapy.
