Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Sydney, Sydney, New South Wales, Australia.
Cancer Res. 2023 Apr 14;83(8):1315-1328. doi: 10.1158/0008-5472.CAN-21-4025.
The inflammatory microenvironment of solid tumors creates a protumorigenic milieu that resembles chronic inflammation akin to a subverted wound healing response. Here, we investigated the effect of converting the tumor microenvironment from a chronically inflamed state to one of acute microbial inflammation by injecting microbial bioparticles directly into tumors. Intratumoral microbial bioparticle injection led to rapid and dramatic changes in the tumor immune composition, the most striking of which was a substantial increase in the presence of activated neutrophils. In situ photoconversion and intravital microscopy indicated that tumor neutrophils transiently switched from sessile producers of VEGF to highly motile neutrophils that clustered to make neutrophil-rich domains in the tumor. The neutrophil clusters remodeled tumor tissue and repressed tumor growth. Single-cell transcriptional analysis of microbe-stimulated neutrophils showed a profound shift in gene expression towards heightened activation and antimicrobial effector function. Microbe-activated neutrophils also upregulated chemokines known to regulate neutrophil and CD8+ T-cell recruitment. Microbial therapy also boosted CD8+ T-cell function and enhanced the therapeutic benefit of checkpoint inhibitor therapy in tumor-bearing mice and provided protection in a model of tumor recurrence. These data indicate that one of the major effector mechanisms of microbial therapy is the conversion of tumor neutrophils from a wound healing to an acutely activated cytotoxic phenotype, highlighting a rationale for broader deployment of microbial therapy in the treatment of solid cancers.
Intratumoral injection of microbial bioparticles stimulates neutrophil antitumor functions, suggesting pathways for optimizing efficacy of microbial therapies and paving the way for their broader utilization in the clinic.
实体瘤的炎症微环境会产生促肿瘤环境，类似于类似于慢性炎症的慢性炎症，类似于被颠覆的伤口愈合反应。在这里，我们通过直接将微生物生物颗粒注入肿瘤来研究将肿瘤微环境从慢性炎症状态转变为急性微生物炎症的效果。肿瘤内微生物生物颗粒注射导致肿瘤免疫成分迅速而明显的变化，其中最显著的是激活的中性粒细胞大量增加。原位光转换和活体显微镜检查表明，肿瘤中性粒细胞暂时从 VEGF 的静止生产者转变为高度运动的中性粒细胞，这些中性粒细胞聚集在肿瘤中形成富含中性粒细胞的区域。中性粒细胞簇重塑了肿瘤组织并抑制了肿瘤生长。对微生物刺激的中性粒细胞的单细胞转录分析显示，基因表达向高度激活和抗菌效应功能发生了深刻转变。微生物激活的中性粒细胞还上调了已知调节中性粒细胞和 CD8+T 细胞募集的趋化因子。微生物疗法还增强了荷瘤小鼠中 CD8+T 细胞的功能，并增强了检查点抑制剂治疗的治疗效果，并为肿瘤复发模型提供了保护。这些数据表明，微生物疗法的主要作用机制之一是将肿瘤中性粒细胞从伤口愈合转变为急性激活的细胞毒性表型，这为优化微生物疗法的疗效提供了依据，并为其在临床中的更广泛应用铺平了道路。
肿瘤内注射微生物生物颗粒刺激中性粒细胞的抗肿瘤功能，提示了优化微生物疗法疗效的途径，并为其在临床中的更广泛应用铺平了道路。
