Tumor immunomodulation by nanoparticle and focused ultrasound alters gut microbiome in a sexually dimorphic manner.

IF 12.4 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Theranostics Pub Date : 2025-01-01 DOI:10.7150/thno.99664
Akansha Singh, Sri Vidhya Chandrasekar, Vishnu Thayil Valappil, Joy Scaria, Ashish Ranjan
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Abstract

Background: Local immunomodulation with nanoparticles (NPs) and focused ultrasound (FUS) is recognized for triggering anti-tumor immunity. However, the impact of these tumor immunomodulations on sex-specific microbiome diversity at distant sites and their correlation with therapeutic effectiveness remains unknown. Here, we conducted local intratumoral therapy using immunogenic cell death-enhancing Calreticulin-Nanoparticles (CRT-NPs) and FUS in male and female mice. We identified immune-related microbiome populations, aiming to translate our findings into clinical applications. Methods: CRT-NPs were synthesized by loading CRT-delivering plasmids into cationic liposomes. Local tumor therapy was performed using CRT-NP and FUS-based histotripsy (HT) on poorly immunogenic Mouse Oral Squamous Cell Carcinoma (MOC2) in the flank regions of male and female mice. Fecal samples were collected and analyzed before and three weeks post-treatment. The microbiome features were then correlated with immune cell dynamics within tumors and systemic cytokine responses to identify prognostic biomarkers in both male and female subjects. Results: Intratumorally administered CRT-NP induced tumor remission and immune cell activation in both male and female mice, whereas HT was ineffective in males and showed efficacy only in females. Turicibacter and Peptococcus inversely correlated with tumor growth, while Enterorhabdus, Subdologranulum, Desulfovibrio, and Aldercreutzia-Asaccharobacter showed direct correlations with tumor growth. HT induced higher levels of Turicibacter in MOC2-bearing females, while males displayed increased Enterorhabdus and Streptococcus populations. Independent of sex, treatments promoting CD4+ T helper cells, functional CD8+ T cells, and total macrophage infiltration correlated with higher levels of Gastrophilales, Romboutsia, Turicibacter, and Peptococcus. Alternatively, Enterorhabdus, Desulfovibrio, Streptococcus, and Staphylococcus corresponded to poor treatment outcomes in both sexes. Conclusion: An enhanced abundance of Enterorhabdus, Desulfovibrio, Streptococcus, and Staphylococcus in response to immunomodulatory therapies could serve as predictive biomarkers in a sex-independent manner. These findings could also be potentially extended to the realm of personalized interventions through fecal transplantations to reverse immunosuppressive phenotypes in males and improve patient outcomes.

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肿瘤免疫调节的纳米粒子和聚焦超声改变肠道微生物在两性二态的方式。
背景:纳米颗粒(NPs)和聚焦超声(FUS)的局部免疫调节被认为是触发抗肿瘤免疫的手段。然而,这些肿瘤免疫调节对远处部位性别特异性微生物群多样性的影响及其与治疗效果的相关性仍不清楚。在这里,我们在雄性和雌性小鼠中使用免疫原性细胞死亡增强钙网蛋白纳米颗粒(CRT-NPs)和FUS进行局部肿瘤内治疗。我们确定了免疫相关的微生物群,旨在将我们的发现转化为临床应用。方法:将传递crt的质粒装入阳离子脂质体中合成CRT-NPs。采用ct - np和基于fuss的组织学(HT)对雌雄小鼠侧腹区免疫原性差的小鼠口腔鳞状细胞癌(MOC2)进行局部肿瘤治疗。在治疗前和治疗后三周收集粪便样本并进行分析。然后将微生物组特征与肿瘤内的免疫细胞动力学和全身细胞因子反应相关联,以确定男性和女性受试者的预后生物标志物。结果:在雄性和雌性小鼠中,瘤内给予CRT-NP诱导肿瘤缓解和免疫细胞活化,而HT在雄性小鼠中无效,仅在雌性小鼠中有效。Turicibacter和Peptococcus与肿瘤生长呈负相关,enterorhabduus、Subdologranulum、Desulfovibrio和Aldercreutzia-Asaccharobacter与肿瘤生长呈直接相关。HT在携带mo2c的雌性中诱导较高水平的Turicibacter,而在雄性中显示出增加的Enterorhabdus和Streptococcus。与性别无关,促进CD4+ T辅助细胞、功能性CD8+ T细胞和总巨噬细胞浸润的治疗与胃杆菌、Romboutsia、Turicibacter和Peptococcus的较高水平相关。另外,肠吸菌、脱硫弧菌、链球菌和葡萄球菌在两性中均表现出较差的治疗效果。结论:肠吸虫、脱硫弧菌、链球菌和葡萄球菌在免疫调节治疗下的丰度增加可以作为一种性别无关的预测性生物标志物。这些发现也可以潜在地扩展到个性化干预领域,通过粪便移植来逆转男性的免疫抑制表型并改善患者的预后。
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来源期刊
Theranostics
Theranostics MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
25.40
自引率
1.60%
发文量
433
审稿时长
1 months
期刊介绍: Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.
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