Mechanoimmunological interactions between TCR-T cells and tumor fibrotic microenvironment

免疫细胞疗法（ACT），包括两种形式：工程化T细胞受体（TCR）疗法 和嵌合抗原受体（CAR）T细胞疗法，目前处于癌症免疫疗法的最前沿。 虽然CAR-T疗法在治疗造血系统癌症方面取得了临床成功， FDA尚未证实其治疗实体瘤的临床疗效。相反，TCR-T细胞 对于实体瘤，治疗似乎更有希望，尽管主要障碍是解除和抑制肿瘤细胞的增殖。 工程化T细胞通过纤维化肿瘤基质，其中含有坚硬且结构复杂的细胞外基质， 细胞基质（ECM）、癌相关成纤维细胞（CAF）和各种免疫细胞（如肿瘤相关的成纤维细胞）。 巨噬细胞（TAM）。随着对TCR-T细胞疗法的深入临床研究， 数量超过了CAR-T治疗的研究，迫切需要了解相互作用的机制 在TCR-T细胞和肿瘤间质之间。本项目的目标是剖析和了解 TCR-T细胞与纤维化肿瘤基质之间的机械免疫相互作用以改善TCR-T 细胞免疫疗法主要假设是抗纤维化策略可以减少肿瘤相关性 纤维化并增强TCR-T细胞克服免疫抑制微环境的能力，从而 从而提高治疗效果。该研究小组由一位医学科学家组成， 靶向肿瘤抗原NY-ESO-1并阻断 免疫抑制TGF-β信号传导的同时，并正在由NIH和DoD资助的临床试验中。的 第二个团队成员是一位生物医学工程师，他专门研究纤维化的器官型模型。 疾病和抗纤维化药物开发。在目前的研究中，新的微生理肿瘤间质小生境 将建立模型来研究TCR-T细胞和纤维化基质因子之间的相互作用 联合或不联合抗纤维化治疗。目的包括研究竞争效应 以确定抑制TCR-T细胞的主要纤维化因子 功能，对肿瘤间质中的动态纤维化进展进行建模，并研究 纤维化抑制、降解和阻断对TCR-T细胞功能的影响， 联合抗纤维化治疗和TCR-T细胞治疗的机制和疗效。这个项目是创新的 因为这项研究剖析了肿瘤纤维化间质抑制转基因TCR-T细胞的机制， 细胞将有助于确定未来纤维化靶向T细胞的设计和优化的治疗靶点 治疗NY-ESO-TCR-T和Super T细胞之间的比较将直接有益于我们正在进行的临床研究。 研究并帮助评估这些治疗性T细胞。预计抗- 纤维化疗法与TCR-T细胞疗法将导致抗癌疗法的新途径， 治疗非免疫原性“冷”肿瘤。

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- fibrosis therapies with TCR-T cell therapy will lead to new avenues of anti-cancer therapy that can become the treatment for nonimmunogenic “cold” tumors.