Mechanoimmunological interactions between TCR-T cells and tumor fibrotic microenvironment

过继细胞疗法(ACT)，包括两种模式：工程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前沿。 虽然CAR-T疗法在治疗造血癌方面取得了临床上的成功，并已获得批准 FDA对实体瘤的临床疗效尚未得到证实。相比之下，TCR-T细胞 实体瘤的治疗方法似乎更有希望，尽管主要障碍是解除和抑制肿瘤。 纤维性肿瘤间质含有僵硬且结构复杂的细胞外基质诱导的T细胞 基质(ECM)、肿瘤相关成纤维细胞(CAF)以及肿瘤相关的各种免疫细胞 巨噬细胞(TAM)。随着对TCR-T细胞疗法的深入正在进行的临床研究 CAR-T疗法的研究数量超过了研究，迫切需要了解相互作用的机制 TCR-T细胞和肿瘤间质之间的关系。本项目的目标是剖析和理解 改良TCR-T细胞与纤维化肿瘤间质的机械免疫相互作用 细胞免疫疗法。主要的假设是，抗纤维化策略可以减少与肿瘤相关的 纤维化，增强TCR-T细胞克服免疫抑制微环境的能力，从而 从而提高了治疗效果。研究团队由一位医学科学家组成，他开创了一种 针对肿瘤抗原NY-ESO-1的双管齐下TCR-T细胞疗法(超级T细胞)并阻断 免疫抑制转化生长因子-β信号的同时，正在由美国国立卫生研究院和国防部资助的临床试验中。这个 第二个团队成员是一名生物医学工程师，专门研究纤维化的器官模型 疾病和抗纤维化药物的开发。在目前的研究中，新的微生理学肿瘤间质生态位 将建立模型来研究TCR-T细胞和纤维化间质因子之间的相互作用 使用和不使用抗纤维化治疗的组合。目的包括调查竞争的影响。 纤维化因子对TCR-T细胞的影响以确定抑制TCR-T细胞的主导纤维化因子 功能，模拟肿瘤间质中的动态纤维化进程，并探讨不同的作用 肝纤维化对TCR-T细胞功能的抑制、降解和阻断及其机制的研究 联合抗纤维化治疗与TCR-T细胞治疗的机制及疗效该项目具有创新性。 因为剖析肿瘤纤维化间质抑制转基因TCR-T的机制的研究 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与Super T细胞的比较将直接有益于我们正在进行的临床 研究并帮助评估这些治疗性T细胞。预计反-联手 TCR-T细胞治疗的纤维化治疗将带来抗癌治疗的新途径，这可能成为 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.