IL-34通过膜受体PDIA3介导膀胱癌CD8+CD103+TRM细胞耗竭的机制

肿瘤微环境免疫稳态失衡与膀胱癌进展密切相关，但调控机制不清。组织原驻记忆T细胞CD8+CD103+TRM是肿瘤微环境重要的免疫细胞成分，在局部发挥保护性免疫功能。我们前期研究中发现：随着膀胱癌的进展，PD1+CD8+CD103+TRM在膀胱癌中的浸润显著增多，但呈耗竭表型。通过转录组测序和后续的功能研究发现：膜受体PDIA3是介导CD8+CD103+TRM细胞耗竭的关键分子，而膀胱癌微环境中IL-34能与膜受体PDIA3结合促进CD8+CD103+TRM细胞耗竭，导致膀胱癌的进展。基于此，本项目拟通过质谱流式绘制膀胱癌免疫微环境图谱，利用临床膀胱癌患者标本、PDIA3 fl/fl CD8 T基因敲除小鼠、原位膀胱癌模型以及多种生物学实验方法，研究IL-34/PDIA3介导CD8+CD103+TRM细胞耗竭的确切作用、临床意义和分子机制，为膀胱癌免疫治疗提供新的思路。

The disbalance of immune homeostasis in tumor microenvironment contributes to bladder cancer progression. The underlying mechanism needs to be investigated systematically. Our previous studies found that the abundance of PD1+CD8+CD103+ TRM, a type of tissue-resident memory CD8+CD103+ T (TRM) cells, increased along with malignant progression of bladder cancer. Importantly, this CD8+CD103+ TRM exhibited the exhausted phenotypic traits, which was correlated with bladder cancer progression. Further, transcriptome sequencing and function related assesses revealed that IL-34 interacted with PDIA3, a membrane receptor, which could be a critical inducer in driving CD8+CD103+ TRM cell exhaustion, whereby leading to bladder cancer progression. Herein, we set up an objective of current study that is: (1) landscaping the atlas of immune cell distribution pattern in immune microenvironment by applying mass cytometry; (2) establishing the correlation between the specific profiling of immune cells in TME with the progressive features by analyzing clinical specimen; (3) by combinatorial using of cellular experiments and a series of animal models including PDIA3 fl/fl CD8 T knockout mice, bladder cancer models, illustrated the molecular mechanism underlying CD8+CD103+ TRM cell exhaustion mediated by IL-34/PDIA3; Moreover, we will conduct an analysis of bladder cancer tissue specimens to confirm the results from abovementioned studies. Collectively, by performing this project, we will generate a set of novel data for pointing out the significance of CD8+CD103+ TRM cell exhaustion in TME of bladder cancer. Hopefully, the original scientific results from current study will be used as a referable information for bladder cancer immunotherapy in the future.