B cell landscape changes during tumour progression

肾细胞癌（RCC）包括一组由肾小管上皮细胞引起的肾癌。在世界范围内，每年有超过40万例RCC病例，其中70%的患者被诊断为透明细胞RCC （ccRCC）。像许多癌症一样，ccRCC产生免疫抑制肿瘤微环境（TME）以逃避免疫系统的消除。虽然调节性T细胞（Tregs）对免疫抑制TME的贡献已经得到了更深入的研究，但对调节性B细胞（Bregs）在癌症进展中所起的作用缺乏了解。我们的目标是使用在ccRCC肿瘤活检和匹配pbmc上进行的单细胞RNA-seq数据来识别驱动Breg募集和抑制活性的tme衍生信号，从而为体外和体内治疗提供靶向这些途径的机会。目的：1)确定B细胞亚群随癌症进展的任何变化，以及这对TME内免疫监视的影响。2)建立与外周血b细胞/Breg共培养的患者源性“类肿瘤”，评估肿瘤对Breg表型/功能的影响3)在小鼠RENCA肾癌模型中是否可以操纵患者体内发现的Breg抑制通路，从而触发肿瘤排斥反应。

Renal cell carcinoma (RCC) encompasses a group of kidney cancers that arise from the epithelial cells lining the renal tubules. Worldwide, there are over 400,000 cases of RCC each year and 70% of patients are diagnosed with clear cell RCC (ccRCC). Like many cancers, ccRCC creates an immunosuppressive tumour microenvironment (TME) to evade elimination by the immune system. Whilst the contribution of regulatory T cells (Tregs) to the immunosuppressive TME has been studied in more depth, there is a lack of understanding of the role played by regulatory B cells (Bregs) in cancer progression. We aim to use single-cell RNA-seq data performed on ccRCC tumour biopsies and matching PBMCs to identify TME-derived signals that drive Breg recruitment and suppressive activity, thus providing the opportunity to target these pathways therapeutically in vitro and in vivo. Aims: 1) to identify any changes in B cell subpopulations as the cancer progresses and what influence this has on immunosurveillance within the TME. 2) to establish patient-derived "tumouroids" co-cultured with peripheral blood Bcells/Bregs to assess the impact of the tumour on Breg phenotype/function 3) To test whether the Breg-inhibiting pathways identified in patients can be manipulated in the murine RENCA renal cancer model to trigger tumour rejection.