Interferon-γ (IFN-γ) is a potent cytokine critical for response to immunotherapy, yet conventional methods to systemically deliver this cytokine have been hindered by severe dose-limiting toxicities. Here, we engineered a strain of probiotic bacteria that home to tumors and locally release IFN-γ. A single intratumoral injection of these IFN-γ–producing bacteria was sufficient to drive systemic tumor antigen–specific antitumor immunity, without observable toxicity. Although cancer cells use various resistance mechanisms to evade immune responses, bacteria-derived IFN-γ overcame primary resistance to programmed cell death 1 (PD-1) blockade via activation of cytotoxic Foxp3 − CD4 + and CD8 + T cells. Moreover, by activating natural killer (NK) cells, bacteria-derived IFN-γ also overcame acquired resistance mechanisms to PD-1 blockade, specifically loss-of-function mutations in IFN-γ signaling and antigen presentation pathways. Collectively, these results demonstrate the promise of combining IFN-γ–producing bacteria with PD-1 blockade as a therapeutic strategy for overcoming immunotherapy-resistant, locally advanced, and metastatic disease.

中文翻译：

---

可编程细菌与 PD-1 阻断协同作用，以克服癌细胞-内在免疫耐药机制


干扰素-γ （IFN-γ） 是一种对免疫治疗反应至关重要的有效细胞因子，但全身递送这种细胞因子的传统方法受到严重剂量限制性毒性的阻碍。在这里，我们设计了一种益生菌菌株，该菌株位于肿瘤并局部释放 IFN-γ。这些产生 IFN γ 的细菌的单次瘤内注射足以驱动全身性肿瘤抗原特异性抗肿瘤免疫，而没有可观察到的毒性。尽管癌细胞使用各种耐药机制来逃避免疫反应，但细菌来源的 IFN-γ 通过激活细胞毒性 Foxp3 − CD4 + 和 CD8 + T 细胞克服了对程序性细胞死亡 1 （PD-1） 阻断的原发性耐药。此外，通过激活自然杀伤 （NK） 细胞，细菌来源的 IFN-γ 还克服了对 PD-1 阻断的获得性耐药机制，特别是 IFN-γ 信号传导和抗原呈递途径的功能丧失突变。总的来说，这些结果表明，将产生 IFN γ的细菌与 PD-1 阻断相结合作为克服免疫治疗耐药、局部晚期和转移性疾病的治疗策略的前景。