Peptide Adjuvant to Invigorate Cytolytic Activity of NK Cells in an Obese Mouse Cancer Model.
Peptide Adjuvant to Invigorate Cytolytic Activity of NK Cells in an Obese Mouse Cancer Model.
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DOI：
10.3390/pharmaceutics13081279
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发表时间：
2021-08-17
期刊：
影响因子：
5.4
通讯作者：
Won YW
中科院分区：
文献类型：
--
作者：
Han S;Jung M;Kim AS;Lee DY;Cha BH;Putnam CW;Lim KS;Bull DA;Won YW
与体重正常的癌症患者相比，超重的癌症患者会出现与肥胖相关的自然杀伤 (NK) 细胞改变，其特点是细胞毒性差、增殖缓慢和抗癌活性不足。与此同时，癌细胞过度表达的抑制素会提高葡萄糖代谢，使肿瘤微环境 (TME) 更有利于肿瘤生长，并导致 TME 中的免疫细胞出现故障。这些变化导致肿瘤生长的恶性循环。过继免疫疗法已成为癌症患者的一个有前途的选择；然而，TME 中与肥胖相关的改变使得肿瘤能够绕过免疫监视并下调过继转移的 NK 细胞的活性。我们假设抑制肥胖模型中的抑制素信号通路会减少癌细胞的葡萄糖代谢，从而将 TME 改变为亲免疫微环境并恢复 NK 细胞的溶细胞活性。用抑制物抑制素结合肽 (PBP) 启动肿瘤细胞可增强细胞因子分泌并增强过继转移的 NK 细胞的溶细胞活性。从 PBP 引发的肿瘤中收获的 NK 细胞表现出与活性 NK 细胞效应功能相关的多种标记。我们的研究结果表明，PBP 有潜力作为佐剂增强肥胖癌症患者过继转移的 NK 细胞的细胞溶解活性。
Cancer patients who are overweight compared to those with normal body weight have obesity-associated alterations of natural killer (NK) cells, characterized by poor cytotoxicity, slow proliferation, and inadequate anti-cancer activity. Concomitantly, prohibitin overexpressed by cancer cells elevates glucose metabolism, rendering the tumor microenvironment (TME) more tumor-favorable, and leading to malfunction of immune cells present in the TME. These changes cause vicious cycles of tumor growth. Adoptive immunotherapy has emerged as a promising option for cancer patients; however, obesity-related alterations in the TME allow the tumor to bypass immune surveillance and to down-regulate the activity of adoptively transferred NK cells. We hypothesized that inhibiting the prohibitin signaling pathway in an obese model would reduce glucose metabolism of cancer cells, thereby changing the TME to a pro-immune microenvironment and restoring the cytolytic activity of NK cells. Priming tumor cells with an inhibitory the prohibitin-binding peptide (PBP) enhances cytokine secretion and augments the cytolytic activity of adoptively transferred NK cells. NK cells harvested from the PBP-primed tumors exhibit multiple markers associated with the effector function of active NK cells. Our findings suggest that PBP has the potential as an adjuvant to enhance the cytolytic activity of adoptively transferred NK cells in cancer patients with obesity.
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