Regression of high endothelial venules manifests sex dimorphism of lymph nodes during aging with implications to anti-tumor immune responses

高内皮小静脉的退化表现出衰老过程中淋巴结的性别二态性，对抗肿瘤免疫反应有影响

• 批准号: 499534188
• 负责人: Dr. Lutz Menzel
• 金额: --
• 依托单位: Department of Radiation Oncology
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/499534188?language=en
• 关键词: Regression; endothelial; venules; manifests; sex

Cancers of non-reproductive tissues occur at a higher frequency in males with a mortality rate twice as high compared to females. This disparity between women and men occurs all across the world, even when the data is adjusted for environmental risk factors and live style. The difference in anti-tumor immune responses is one determining factor of the sex-biased cancer incidence. However, how the innate and adaptive immune system engage with cancer as determined by sex and age is still poorly understood. My preliminary data show a regression of LTbR/NFkB-maintained high endothelial venules (HEV) and a subsequent decline of LN volume and cellularity that occurs in both sexes but earlier in live in males. I hypothesize that female gonadal hormones stimulate HEVs directly or via transcriptional regulation by secondary factors. Single-cell RNA sequencing data of LNs from middle-aged and older individuals revealed that osteopontin (OPN) is differentially expressed in HEV cells of females compared to males. Acting as an intracellular stabilizer of the NFkB pathway, OPN appears to be a promising candidate involved in HEV maintenance in female LNs. I further hypothesize that the smaller population size of naïve T cells in male LNs causes a more restricted TCR repertoire in tumor draining LNs, which might play a part in the inferior anti-tumor immunity and the male predominance in cancer incidence and mortality. In the proposed project, I will measure sex-disparities of LNs sizes, investigate sex and age-related mechanisms that dictate these differences and assess implications for anti-tumor immune responses.

非生殖组织癌症在男性中发生的频率更高，死亡率是女性的两倍。男女之间的这种差异在世界各地都存在，即使数据经过环境风险因素和生活方式的调整。抗肿瘤免疫反应的差异是性别偏见癌症发病率的一个决定因素。然而，先天性和适应性免疫系统如何与癌症结合，由性别和年龄决定，仍然知之甚少。我的初步数据显示，回归LTbR/NF κ B维持高内皮微静脉（HEV）和随后的LN体积和细胞的下降，发生在两种性别，但更早地在男性的生活。我推测，女性性腺激素刺激HEVs直接或通过转录调控的次要因素。来自中老年个体的LN的单细胞RNA测序数据显示，与男性相比，骨桥蛋白（OPN）在女性的HEV细胞中差异表达。作为NFkB通路的细胞内稳定剂，OPN似乎是参与女性LN中HEV维持的有希望的候选者。我进一步假设，男性淋巴结中幼稚T细胞的群体规模较小，导致肿瘤引流淋巴结中TCR库更受限制，这可能在抗肿瘤免疫力低下以及男性在癌症发病率和死亡率方面占优势方面发挥作用。在拟议的项目中，我将测量淋巴结大小的性别差异，研究决定这些差异的性别和年龄相关机制，并评估抗肿瘤免疫反应的影响。