Adoptive cellular therapies (ACT), including the two modalities: Engineered T Cell Receptor (TCR) Therapy and Chimeric Antigen Receptor (CAR) T Cell Therapy, are currently at the forefront of cancer immunotherapy. While CAR-T therapies has gained clinical success in the treatment of hemopoietic cancers and are approved by FDA, the clinical efficacy for treatment of solid tumors has not been confirmed. In contrast, TCR-T Cell therapies seem more promising for solid tumors, though a main barrier is the disarmament and suppression of the engineered T cells by the fibrotic tumor stroma that contains stiff and structurally-complex extracellular matrix (ECM), cancer associated fibroblasts (CAFs) and various immune cells such as tumor associated macrophages (TAMs). With intensive ongoing clinical investigations on the TCR-T cell therapies that outnumbers the studies on CAR-T therapy, there is an urgent need to understand the mechanism of interaction between TCR-T cells and the tumor stroma. The objective of this project is to dissect and understand the mechano-immunological interaction between TCR-T cells and the fibrotic tumor stroma for improved TCR-T cell immunotherapies. The main hypothesis is that the anti-fibrosis strategies can reduce tumor-associated fibrosis and enhance the ability of TCR-T cells to overcome the immunosuppressive microenvironment, thus leading to improved therapeutic efficacy. The research team consists of a medical scientist who pioneered a two-pronged TCR-T cell therapy (super T cell) that targets tumor antigen NY-ESO-1 and blocks immunosuppressive TGF-β signaling at the same time and is under clinical trials funded by NIH and DoD. The second team member is a biomedical engineer who is specialized in the organotypic modeling of fibrotic diseases and anti-fibrosis drug development. In the current study, novel microphysiological tumor stroma niche models will be developed to investigate the interaction between TCR-T cells and the fibrotic stromal factors with and without the combination of anti-fibrosis therapies. The aims include investigating the competing effect of fibrotic factors on the TCR-T cells to determine the dominant fibrotic factors that suppress the TCR-T cell functions, modeling the dynamic fibrosis progression in the tumor stroma and investigate the different effect of fibrosis inhibition, degradation and blockade on the functions of the TCR-T cells and investigating the mechanism and efficacy of combined anti-fibrosis therapy and TCR-T cell therapy. This project is innovative because the study to dissect the mechanism by which tumor fibrotic stroma suppresses the transgenic TCR-T cells will help to identify the therapeutic targets for the design and optimization of future fibrosis-targeting T cell therapies. The comparison between NY-ESO-TCR-T and Super T cells will directly benefit our ongoing clinical study and help with the evaluation of these therapeutic T cells. It is expected that the combination of anti-...