Intra-tumoral delivery of 5'ppp-dsRNA induces robust anti-tumor response via RIG-I activation and Bcl-2 gene downregulation in murine model of prostate cancer.

IF 4.8 4区 医学 Q2 IMMUNOLOGY International immunology Pub Date : 2024-10-10 DOI:10.1093/intimm/dxae061
Kasturi Ganguly, Siddhanath M Metkari, Barnali Biswas, Rambhadur Subedi, Taruna Madan
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引用次数: 0

Abstract

Onco-immunotherapy via blocking checkpoint-inhibitors has revolutionized the treatment-landscape of several malignancies, though not in the metastatic castration-resistant prostate cancer (PCa) owing to immunosuppressive and poorly immunogenic "cold" tumor microenvironment (TME). Turning up the heat of such cold TME via triggering innate immunity is now of increasing interest to restore immune-surveillance. Retinoic acid-inducible gene- I (RIG-I)-like receptors (RLRs) are cytosolic innate-sensors that can detect exogenous RNAs and induce type-I interferons and other pro-inflammatory signaling. RIG-I activation is suggested to be a valuable addition to the treatment approaches for several cancers. However, the knowledge about RIG-I signaling in PCa remains elusive. The present study evaluated the expression of two important RLRs, RIG-I and melanoma differentiation-associated protein 5 (MDA5) along with their downstream partners, mitochondrial antiviral-signaling protein (MAVS) and ERA G-protein-like 1 (ERAL1) during PCa progression in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. The early stage of PCa revealed a significant increment in the expression of RLRs, but not MAVS. However, the advanced stage showed downregulated RLR signaling. Further, the therapeutic implication of 5'ppp-dsRNA, a synthetic RIG-I agonist and Bcl2 gene silencer has been investigated in vitro and in vivo. Intra-tumoral delivery of 5'ppp-dsRNA regressed tumor growth via triggering tumor cells apoptosis, immunomodulation, and inducing phagocytic "eat me" signals. These findings highlight that, for the first time, RIG-I activation and Bcl-2 silencing with 5'ppp-dsRNA can serve as a potent tumor-suppressor strategy in PCa and has a significant clinical implication in transforming "cold" TME into immunogenic "hot" TME of PCa.

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在小鼠前列腺癌模型中,5'ppp-dsRNA 的瘤内给药通过 RIG-I 激活和 Bcl-2 基因下调诱导强有力的抗肿瘤反应。
通过阻断检查点抑制剂进行的肿瘤免疫疗法已经彻底改变了多种恶性肿瘤的治疗前景,但由于肿瘤微环境(TME)具有免疫抑制作用且免疫原性较差,因此并不适用于转移性耐受性前列腺癌(PCa)。通过激发先天性免疫来改善这种 "冷 "肿瘤微环境,以恢复免疫监视,现在越来越受到人们的关注。视黄酸诱导基因 I(RIG-I)样受体(RLRs)是一种细胞膜先天性感应器,可检测外源性 RNA 并诱导 I 型干扰素和其他促炎信号传导。有人认为,RIG-I 激活是治疗多种癌症的一种重要方法。然而,人们对PCa中RIG-I信号转导的了解仍然有限。本研究在转基因小鼠前列腺腺癌(TRAMP)模型中评估了PCa进展过程中两个重要的RLRs(RIG-I和黑色素瘤分化相关蛋白5(MDA5))及其下游伙伴线粒体抗病毒信号蛋白(MAVS)和ERA G蛋白样1(ERAL1)的表达情况。在 PCa 早期,RLRs 的表达显著增加,但 MAVS 的表达却没有增加。然而,晚期则显示 RLR 信号下调。此外,还在体外和体内研究了合成 RIG-I 激动剂和 Bcl2 基因沉默器 5'ppp-dsRNA 的治疗意义。通过引发肿瘤细胞凋亡、免疫调节和诱导吞噬细胞发出 "吃我 "信号,5'ppp-dsRNA 的瘤内给药抑制了肿瘤的生长。这些研究结果突出表明,用5'ppp-dsRNA激活RIG-I和沉默Bcl-2可作为一种有效的PCa肿瘤抑制策略,在将PCa的 "冷 "TME转化为免疫原性 "热 "TME方面具有重要的临床意义。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
International immunology
International immunology 医学-免疫学
CiteScore
9.30
自引率
2.30%
发文量
51
审稿时长
6-12 weeks
期刊介绍: International Immunology is an online only (from Jan 2018) journal that publishes basic research and clinical studies from all areas of immunology and includes research conducted in laboratories throughout the world.
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