Tumor immunity in prostate cancer (PCa): Novel treatment approaches based on CD40-CD40L interactions

前列腺癌（PCa）是男性中最具威胁性的癌症之一，在其一生中有六分之一的男性被诊断出。常规疗法通常仅诱导短暂的治疗效果，特别是在激素非依赖性PCa的情况下。迫切需要开发新的有效的PCa治疗方法和新的生物标志物。因此，在这项联合拨款申请中，我们的目标是开发新的治疗策略，靶向低免疫原性PCa的基础上的新抗原ZP 3，表达在PCa和触发免疫增强CD 40/CD 40 L信号轴。针对肿瘤-间质和免疫细胞之间复杂的动态相互作用、各种功能性不同的CD 40/CD 40 L相互作用以及PCa对慢性炎症微环境的敏感性，建立了多学科研究团队，在肿瘤免疫学方面进行以下方面的研究：I. CD 40连接对肿瘤-基质和由表达CD 8+辅助T细胞的CD 40 L提供的免疫细胞的影响II.间质成纤维细胞对CD 40/CD 40 L介导的T细胞活化的负调节，尤其是在性激素或炎性细胞因子III存在的情况下。基于靶向CD 40/CD 40 L通路和ZP 3相互作用的肿瘤排斥诱导以及ZP 3作为PCa潜在生物标志物的建立相关项目将揭示关于肿瘤-基质如何通过产生的肿瘤抗原特异性免疫应答有效靶向的机制以及哪些因素影响这些相互作用的基本知识。与这些获得的结果一起，新的PCa特异性抗原ZP 3在所有三个子项目中的应用和验证可能导致建立PCa的预后生物标志物和新的免疫治疗选择。

Prostate cancer (PCa) is one of the most threatening cancers in men, diagnosed in one of six men during their lifetimes. Conventional therapies often only induce transient therapeutic effects, particularly in the case of hormone independent PCa. There is an urgent need to develop novel efficient PCa treatment approaches and novel biomarkers. Consequently, in this joint grant application we aim to develop novel treatment strategies targeting low immunogenic PCa based on the novel antigen ZP3, expressed on PCa and on triggering the immunopotentiating CD40/CD40L signal axis. In respect of the complex dynamic interplay between tumor-stroma and immune cells, the various functional different CD40/CD40L interactions, and the sensitivity of PCa to a chronic inflammatory microenvironment a multi-disciplinary research team is established to investigate following aspects in tumor immunology:I. Impact of CD40 ligation on tumor-stroma and immune cells provided by CD40L expressing CD8+ Helper T cellsII. Negative regulation of CD40/CD40L mediated T-cell activation by stromal fibroblasts, especially in the presence of sexual hormones or inflammatory cytokinesIII. Induction of tumor rejection based on targeting CD40/CD40L pathways and ZP3 interactions and establishment of ZP3 as a potential biomarker of PCaThe connected projects will reveal essential knowledge about the mechanisms how tumor-stroma is targeted efficiently by generated tumor-antigen specific immune responses and which factors influence these interactions. Together with these obtained results, the application and validation of the novel PCa-specific antigen ZP3 in all three subprojects may lead to the establishment of prognostic biomarkers and novel immunotherapy options for PCa.