Anti-CD47 tri-specific killer engager enhances NK cell cytotoxicity against lung cancer.

IF 2.7 3区 医学 Q2 ONCOLOGY
Chutipa Chiawpanit, Yupanun Wutti-In, Somsakul Pop Wongpalee, Ratchaneewan Sumankan, Peeranut Winidmanokul, Prin Sungwan, Seiji Okada, Naravat Poungvarin, Pa-Thai Yenchitsomanus, Aussara Panya
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Abstract

Lung cancer remains the leading cause of cancer-related deaths worldwide, with immune evasion posing a major therapeutic challenge. One key mechanism involves the 'don't eat me' signal mediated by the interaction between CD47 and signal regulatory protein alpha (SIRPα), which inhibits macrophage phagocytosis and natural killer (NK) cell cytotoxicity, facilitating tumor escape. To overcome this immune evasion, we developed a tri-specific killer engager (TriKE) targeting CD47, termed anti-CD47 TriKE, designed to enhance NK cell-mediated cytotoxicity against lung cancer cells. The activity of anti-CD47 TriKE was evaluated for its ability to induce NK cell proliferation and its binding affinity to NK cells and lung cancer cell lines (A549, NCI-H460, and NCI-H1975). At a concentration of 30 nM, anti-CD47 TriKE effectively promoted NK cell proliferation and exhibited strong binding to both NK cells and lung cancer cells. Functional assays in 2D and 3D co-culture models demonstrated that anti-CD47 TriKE significantly enhanced NK cell specificity and cytotoxicity. Notably, NK cell-mediated cytotoxicity correlated with the basal level of CD47 expression in target cells. In NCI-H1975 cells, which exhibit the highest CD47 expression, target cell viability was reduced by approximately 40%-a significantly greater reduction than in control groups. These findings highlight the potential of anti-CD47 TriKE as a promising immunotherapeutic strategy for lung cancer, particularly in targeting high-CD47-expressing tumor cells and overcoming immune evasion mechanisms.

抗cd47三特异性杀手接合物增强NK细胞对肺癌的细胞毒性。
肺癌仍然是世界范围内癌症相关死亡的主要原因,免疫逃避构成了一个重大的治疗挑战。其中一个关键机制涉及由CD47和信号调节蛋白α (SIRPα)相互作用介导的“不要吃我”信号,该信号抑制巨噬细胞吞噬和自然杀伤细胞(NK)细胞毒性,促进肿瘤逃逸。为了克服这种免疫逃避,我们开发了一种靶向CD47的三特异性杀手参与器(TriKE),称为抗CD47 TriKE,旨在增强NK细胞介导的对肺癌细胞的细胞毒性。抗cd47 TriKE的活性评估了其诱导NK细胞增殖的能力以及与NK细胞和肺癌细胞系(A549, NCI-H460和NCI-H1975)的结合亲和力。在浓度为30 nM时,抗cd47 TriKE可有效促进NK细胞增殖,并与NK细胞和肺癌细胞均表现出较强的结合。2D和3D共培养模型的功能分析表明,抗cd47 TriKE显著增强NK细胞特异性和细胞毒性。值得注意的是,NK细胞介导的细胞毒性与靶细胞中CD47的基础表达水平相关。在CD47表达最高的NCI-H1975细胞中,靶细胞活力降低了约40%,显著高于对照组。这些发现强调了抗cd47 TriKE作为一种有前途的肺癌免疫治疗策略的潜力,特别是在靶向高cd47表达的肿瘤细胞和克服免疫逃避机制方面。
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
CiteScore
7.60
自引率
0.00%
发文量
121
审稿时长
1 months
期刊介绍: The development of new anticancer agents is one of the most rapidly changing aspects of cancer research. Investigational New Drugs provides a forum for the rapid dissemination of information on new anticancer agents. The papers published are of interest to the medical chemist, toxicologist, pharmacist, pharmacologist, biostatistician and clinical oncologist. Investigational New Drugs provides the fastest possible publication of new discoveries and results for the whole community of scientists developing anticancer agents.
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