Bacterial immunotherapy leveraging IL-10R hysteresis for both phagocytosis evasion and tumor immunity revitalization [ATAC-seq]

Bacterial immunotherapy holds promising cancer-fighting potential. However, unlocking its power requires a mechanistic understanding of how bacteria both evade antimicrobial immune defenses and stimulate antitumor immune responses within the tumor microenvironment (TME). Here, by harnessing an engineered Salmonella enterica strain with this dual proficiency, we unveiled a singular mechanism underlying. Specifically, the hysteretic nonlinearity of interleukin-10 receptor (IL-10R) expression drives tumor-infiltrated immune cells into a tumor-specific IL-10Rhi state. Bacteria leverage this to enhance tumor-associated macrophages producing IL-10, evade phagocytosis by tumor-associated neutrophils, and coincidently expand and stimulate the preexisting exhausted tumor-resident CD8+ T cells. This effective combination eliminated tumors, prevented recurrence, and inhibited metastasis across multiple tumor types. Analysis of human samples suggested that IL-10Rhi state might be a ubiquitous trait across human tumor types. Our study unveils the unsolved mechanism behind bacterial immunotherapy's dual challenge in solid tumors and provides a framework for intratumor immunomodulation. Jurkat T cells were divided into four groups: Pre-exposure (direct sample collection), Initial exposure (stimulated with 10 ng/ml IL-10 for 6 h), Rest (stimulated with 10 ng/ml IL-10 for 6 h, washed, and cultured for 48 h in 0.5 ng/ml IL-10 with medium changes every 12 h), and Subsequent exposure (same as Rest, with an additional 6-h stimulation with 10 ng/ml IL-10)

细菌免疫疗法具备极具潜力的抗肿瘤治疗前景。然而，若要充分释放其治疗效能，必须阐明细菌在肿瘤微环境（tumor microenvironment, TME）中如何规避抗菌免疫防御、同时激活抗肿瘤免疫应答的内在机制。
本研究通过构建兼具上述双重功能的工程化鼠伤寒沙门氏菌（Salmonella enterica）菌株，揭示了其背后的独特作用机制。具体而言，白细胞介素-10受体（interleukin-10 receptor, IL-10R）表达的迟滞非线性特征，可将肿瘤浸润免疫细胞诱导为肿瘤特异性IL-10R高表达（IL-10Rhi）状态。
细菌可利用这一状态，促进肿瘤相关巨噬细胞分泌白细胞介素-10（IL-10），规避肿瘤相关中性粒细胞的吞噬作用，同时扩增并激活机体内已存在的组织驻留耗竭型CD8+ T细胞。该有效策略可在多种肿瘤模型中实现实体瘤清除、预防肿瘤复发并抑制肿瘤转移。
对人类临床样本的分析显示，IL-10R高表达状态可能广泛存在于各类人类肿瘤中。本研究阐明了细菌免疫疗法在实体瘤中面临的双重挑战背后尚未被揭示的核心机制，同时为肿瘤内免疫调控提供了全新的研究框架。
将Jurkat T细胞分为四组：预暴露组（直接收集样本）、初始暴露组（以10 ng/ml的IL-10刺激6小时）、恢复组（以10 ng/ml的IL-10刺激6小时后洗涤细胞，随后在0.5 ng/ml的IL-10中培养48小时，每12小时更换一次培养基）以及后续暴露组（操作流程与恢复组一致，额外以10 ng/ml的IL-10刺激6小时）