Melissa Maxwell, Dingxue Yan, Brianna Rivest, Andrew Boone, James Cardia, Elfriede Noessner
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引用次数: 0
摘要
自然杀伤(NK)细胞是抗癌的前线卫士,能够识别并消灭肿瘤细胞,而无需事先进行致敏或抗原递呈。由于其独特的 HLA 错配耐受性,它们是采用细胞疗法 (ACT) 的理想选择,因为它们能够最大限度地降低移植物抗宿主疾病的风险。NK 细胞的疗效部分受到抑制性免疫检查点受体的限制,这些受体在与癌细胞和肿瘤微环境相互作用时会上调。抑制性受体的过度表达会损害 NK 细胞分泌效应细胞因子和细胞毒性颗粒的能力,从而降低 NK 细胞介导的细胞毒性。具有免疫球蛋白和 ITIM 结构域的 T 细胞免疫受体(TIGIT)是众所周知的参与 T 细胞衰竭的检查点受体,最近也被认为与 NK 细胞的衰竭有关。克服 TIGIT 介导的 NK 细胞抑制可能使 ACT 后的抗肿瘤反应更有效。在这里,我们介绍了一种利用自传递 RNAi 化合物(INTASYL™)抑制 TIGIT 的新方法,该方法结合了 RNAi 和反义技术的特点。INTASYL 化合物具有强大的活性和稳定性,能快速、高效地被细胞吸收,并能方便地融入细胞产品生产中。INTASYL PH-804 以 TIGIT 为靶标,可抑制 NK 细胞中 TIGIT mRNA 和蛋白的表达,从而提高细胞毒性能力,增强体外杀伤肿瘤细胞的能力。在 ACT 前向 NK 细胞释放 PH-804 已成为对抗 TIGIT 抑制从而改善抗肿瘤反应的一种有前途的策略。这种方法有望为采用细胞疗法,特别是血液恶性肿瘤的治疗提供更有效的现成产品。
INTASYL self-delivering RNAi decreases TIGIT expression, enhancing NK cell cytotoxicity: a potential application to increase the efficacy of NK adoptive cell therapy against cancer.
Natural killer (NK) cells are frontline defenders against cancer and are capable of recognizing and eliminating tumor cells without prior sensitization or antigen presentation. Due to their unique HLA mismatch tolerance, they are ideal for adoptive cell therapy (ACT) because of their ability to minimize graft-versus-host-disease risk. The therapeutic efficacy of NK cells is limited in part by inhibitory immune checkpoint receptors, which are upregulated upon interaction with cancer cells and the tumor microenvironment. Overexpression of inhibitory receptors reduces NK cell-mediated cytotoxicity by impairing the ability of NK cells to secrete effector cytokines and cytotoxic granules. T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), a well-known checkpoint receptor involved in T-cell exhaustion, has recently been implicated in the exhaustion of NK cells. Overcoming TIGIT-mediated inhibition of NK cells may allow for a more potent antitumor response following ACT. Here, we describe a novel approach to TIGIT inhibition using self-delivering RNAi compounds (INTASYL™) that incorporates the features of RNAi and antisense technology. INTASYL compounds demonstrate potent activity and stability, are rapidly and efficiently taken up by cells, and can be easily incorporated into cell product manufacturing. INTASYL PH-804, which targets TIGIT, suppresses TIGIT mRNA and protein expression in NK cells, resulting in increased cytotoxic capacity and enhanced tumor cell killing in vitro. Delivering PH-804 to NK cells before ACT has emerged as a promising strategy to counter TIGIT inhibition, thereby improving the antitumor response. This approach offers the potential for more potent off-the-shelf products for adoptive cell therapy, particularly for hematological malignancies.
期刊介绍:
Cancer Immunology, Immunotherapy has the basic aim of keeping readers informed of the latest research results in the fields of oncology and immunology. As knowledge expands, the scope of the journal has broadened to include more of the progress being made in the areas of biology concerned with biological response modifiers. This helps keep readers up to date on the latest advances in our understanding of tumor-host interactions.
The journal publishes short editorials including "position papers," general reviews, original articles, and short communications, providing a forum for the most current experimental and clinical advances in tumor immunology.