PO.CL06.02 · 临床研究
靶向Yap1-B7-H3信号在雄性SHH髓母细胞瘤中优先刺激CD8⁺抗肿瘤反应
Targeting Yap1 -B7-H3 signaling stimulates CD8⁺ anti-tumor response preferentially in male SHH medulloblastoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
癌症中的性别偏倚机制仍知之甚少。我们最近报道了Yap1（一种在许多人类癌症中失调的癌基因）在SHH髓母细胞瘤（MB）小鼠模型中一种出人意料的性别偏倚功能。Yap1缺失优先在雄性动物中显著延长生存期并增强免疫浸润，部分是通过减弱MB细胞中免疫检查点分子Cd276（B7-H3）的表达来实现的。这些发现具有临床意义，因为患有MB（最常见的儿科脑恶性肿瘤）的男性患者表现出更差的生存期和更高的发病率。
在此，我们研究Yap1缺失的性别特异性后果，并评估使用系统性给药的CD276靶向化学自组装纳米环（CD276-CSAN）对CD276进行治疗性靶向。
通过单细胞RNA测序和高参数流式细胞术对Yap1缺失的雄性和雌性肿瘤中的免疫微环境进行的广泛表征显示，雄性中表现出细胞毒性特性的CD8+ T细胞显著增加，而雌性中则没有。相反，Yap1缺失的雌性具有更高数量的耗竭CD8+ T细胞和调节性T细胞。此外，体内CD8 T细胞清除消除了Yap1缺失雄性MB中所见的生存优势，证实了这些细胞的功能重要性。
T细胞增殖实验表明，在雄性MB细胞中，靶向Yap1或CD276均可恢复T细胞活化。相反，基线CD276表达较高的雌性则需要同时进行Yap1缺失和CD276阻断/缺失才能实现类似的活化。与此一致，用CD276-CSAN进行CD276阻断表型上重现了Yap1缺失的雄性偏倚生存优势，并在体内增加了CD8+ T细胞浸润。
总体而言，这些发现揭示了Yap1通过Cd276介导的CD8+ T细胞抑制促进雄性偏倚的MB进展，导致免疫逃逸，并突出CD276作为改善雄性MB预后的有前景的治疗靶点。
*同等贡献
查看英文原文 English abstract
Sex-biased mechanisms in cancer remain poorly understood. We recently reported an unexpected sex-biased function of Yap1 , an oncogene dysregulated in many human cancers, in murine models of SHH medulloblastoma (MB). Yap1 deletion significantly extends survival preferentially in male animals and enhances immune infiltration, in part by attenuating the expression of the immune checkpoint molecule Cd276 (B7-H3) in MB cells. These findings are clinically relevant because male patients with MB, the most common pediatric brain malignancy, exhibit worse survival and a higher incidence.
Here, we investigate the sex-specific consequences of Yap1 loss and evaluate therapeutic targeting of CD276 using systemically administered CD276-targeting chemically self-assembled nanorings (CD276-CSANs).
Extensive characterization of the immune microenvironment in Yap1 -deleted male and female tumors, conducted via single-cell RNA sequencing and high-parameter flow cytometry, revealed a significant increase in CD8+ T cells exhibiting cytotoxic properties in males, but not in females. In contrast, Yap1 -deleted females had higher numbers of exhausted CD8+ T cells and regulatory T cells. Further, in vivo CD8 T cell depletion abolished the survival advantage seen in Yap1 -deleted male MB, confirming the functional importance of these cells.
T-cell proliferation assays demonstrated that in male MB cells, targeting either Yap1 or CD276 restored T-cell activation. In contrast, females, which have higher baseline CD276 expression, required both Yap1 deletion and CD276 blockade/deletion to achieve similar activation. Consistently, CD276 blockade with CD276-CSANs phenocopied the male-biased survival advantage of Yap1 deletion and increased CD8+ T-cell infiltration in vivo .
Overall, these findings reveal that Yap1 promotes male-biased MB progression via Cd276 -mediated CD8+ T cell suppression, resulting in immune evasion and highlighting CD276 as a promising therapeutic target for improving male MB prognosis.
*contributed equally
利益披露 Disclosure
N. Abdelfattah*, None..
M. Faisal*, None..
H. N. Tran, None..
T. Wong, None..
F. Rodriguez, None.
C. R. Wagner,
Tychon Bioscience, Inc. Other, Founder, Chief Scientific Officer, Shareholder; this company has licensed patents from the University of Minnesota related to the CD276-CSAN described in this abstract.
K. Yun,
EMPIRI, Inc Other, Co-founder.