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一，一生中有六分之一的男性被诊断出患有前列腺癌。传统的治疗方法往往只能诱导短暂的治疗效果，特别是在激素不依赖型PCa的情况下。迫切需要开发新的有效的前列腺癌治疗方法和新的生物标志物。因此，在这项联合资助申请中，我们的目标是基于新型抗原ZP3开发针对低免疫原性前列腺癌的新型治疗策略，该抗原在前列腺癌上表达并触发免疫增强的CD40/CD40L信号轴。针对肿瘤-基质与免疫细胞之间复杂的动态相互作用，各种功能不同的CD40/CD40L相互作用，以及前列腺癌对慢性炎症微环境的敏感性，组建多学科研究团队，在肿瘤免疫学方面开展以下研究：CD40结扎对表达CD8+辅助性T细胞的CD40L提供的肿瘤基质和免疫细胞的影响间质成纤维细胞对CD40/CD40L介导的t细胞活化的负调控，特别是在性激素或炎性细胞因子存在的情况下。基于靶向CD40/CD40L通路和ZP3相互作用的肿瘤排斥诱导以及ZP3作为pca潜在生物标志物的建立。相关项目将揭示肿瘤-基质如何通过产生肿瘤抗原特异性免疫反应有效靶向的机制以及影响这些相互作用的因素。结合这些获得的结果，新型PCa特异性抗原ZP3在所有三个子项目中的应用和验证可能会导致PCa预后生物标志物和新的免疫治疗选择的建立。

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.