Danielson Meggie, Nicolai Christopher J, Vo Thaomy T, Wolf Natalie K, Burke Thomas P
Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA 92617, USA.
Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
iScience. 2024 Nov 13;27(12):111385. doi: 10.1016/j.isci.2024.111385. eCollection 2024 Dec 20.
Intracellular bacterial pathogens are distinctive tools for fighting cancer, as they can proliferate in tumors and deliver therapeutic payloads to the eukaryotic cytosol. Cytosol-dwelling bacteria have undergone extensive preclinical and clinical testing, yet the mechanisms of activating innate immunity in tumors are unclear. We report that phylogenetically distinct cytosolic pathogens, including , , and species, elicited anti-tumor responses in poorly immunogenic melanoma and lymphoma in mice. Although the bacteria required cytosolic access, anti-tumor responses were largely independent of the cytosolic sensors cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING), but instead required Toll-like receptor (TLR) signaling. Combining pathogens with STING agonists elicited profound, synergistic anti-tumor effects with complete responses in >80% of mice. Small molecule TLR agonists also synergistically enhanced STING agonists. The responses required RAG2 but not interferons, and cured mice developed immunity to cancer rechallenge requiring CD8 T cells. These studies provide a framework for enhancing microbial and small molecule innate agonists for cancer, via co-activating STING and TLRs.
细胞内细菌性病原体是对抗癌症的独特工具，因为它们可以在肿瘤中增殖并将治疗性载荷递送至真核细胞溶质中。寄居于细胞溶质的细菌已进行了广泛的临床前和临床测试，但其在肿瘤中激活先天免疫的机制尚不清楚。我们报告称，包括 、 和 物种在内的系统发育上不同的细胞溶质病原体在免疫原性较差的小鼠黑色素瘤和淋巴瘤中引发了抗肿瘤反应。尽管细菌需要进入细胞溶质，但抗肿瘤反应在很大程度上独立于细胞溶质传感器环磷酸鸟苷-腺苷酸合成酶（cGAS）和干扰素基因刺激物（STING），而是需要Toll样受体（TLR）信号传导。将病原体与STING激动剂联合使用可引发深刻的协同抗肿瘤作用，超过80%的小鼠出现完全反应。小分子TLR激动剂也能协同增强STING激动剂。这些反应需要重组激活基因2（RAG2）而不是干扰素，治愈的小鼠对癌症再激发产生免疫力，这需要CD8 T细胞。这些研究为通过共同激活STING和TLR来增强用于癌症治疗的微生物和小分子先天激动剂提供了一个框架。
