Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Immunology Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Front Immunol. 2023 Jun 28;14:1211730. doi: 10.3389/fimmu.2023.1211730. eCollection 2023.
Intracellular recognition of self and non-self -nucleic acids can result in the initiation of effective pro-inflammatory and anti-tumorigenic responses. We hypothesized that macrophages can be activated by tumor-derived nucleic acids to induce inflammasome activation in the tumor microenvironment. We show that tumor conditioned media (CM) can induce IL-1β production, indicative of inflammasome activation in primed macrophages. This could be partially dependent on caspase 1/11, AIM2 and NLRP3. IL-1β enhances tumor cell proliferation, migration and invasion while coculture of tumor cells with macrophages enhances the proliferation of tumor cells, which is AIM2 and caspase 1/11 dependent. Furthermore, we have identified that DNA-RNA hybrids could be the nucleic acid form which activates AIM2 inflammasome at a higher sensitivity as compared to dsDNA. Taken together, the tumor-secretome stimulates an innate immune pathway in macrophages which promotes paracrine cancer growth and may be a key tumorigenic pathway in cancer. Broader understanding on the mechanisms of nucleic acid recognition and interaction with innate immune signaling pathway will help us to better appreciate its potential application in diagnostic and therapeutic benefit in cancer.
细胞内对自身和非自身的识别-核酸可以引发有效的促炎和抗肿瘤反应。我们假设肿瘤来源的核酸可以激活巨噬细胞，在肿瘤微环境中诱导炎症小体激活。我们表明，肿瘤条件培养基（CM）可以诱导 IL-1β 的产生，表明在被激活的巨噬细胞中炎症小体的激活。这可能部分依赖于半胱天冬酶 1/11、AIM2 和 NLRP3。IL-1β 增强肿瘤细胞的增殖、迁移和侵袭，而肿瘤细胞与巨噬细胞的共培养增强了肿瘤细胞的增殖，这依赖于 AIM2 和半胱天冬酶 1/11。此外，我们已经确定，与双链 DNA 相比，DNA-RNA 杂交体可能是激活 AIM2 炎症小体的核酸形式，其敏感性更高。总之，肿瘤分泌组刺激巨噬细胞中的先天免疫途径，促进旁分泌肿瘤生长，这可能是癌症中的一个关键致癌途径。对核酸识别和与先天免疫信号通路相互作用机制的更深入了解将有助于我们更好地理解其在癌症诊断和治疗中的潜在应用。
