肿瘤细胞治疗研究
英文原题：Antitumor effects of NK cells expanded by activation pre‑processing of autologous feeder cells before irradiation in colorectal cancer.
Antitumor effects of NK cells expanded by activation pre‑processing of autologous feeder cells before irradiation in colorectal cancer.
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自然杀伤（NK）细胞在针对转化细胞的早期免疫防御中发挥关键作用，并用于癌症的治疗管理。然而，难以充分获得高纯度的活化NK细胞用于临床应用。NK细胞的功能依赖于活化信号与抑制信号的平衡。需要强烈且多样的刺激来增强NK细胞的功能。放疗调节多种免疫调节分子的表达，这些分子可招募并活化NK细胞。NK细胞介导的抗体依赖性细胞毒性是NK细胞针对靶癌细胞最强的细胞毒性效应之一。为了生成活化和照射后的自体外周血单核细胞（PBMCs），本研究进行了细胞因子和单克隆抗体刺激，随后进行电离辐射。扩增的NK细胞使用活化的/照射后的自体PBMCs培养21天。使用结直肠癌细胞（SW480和HT-29）分析放疗对NK group 2D配体和EGFR表达的影响。使用流式细胞术分析放疗联合基于NK细胞的靶向治疗对结直肠癌细胞系的细胞毒性。活化和照射后的PBMCs表现出多种刺激NK细胞的活化配体表达显著增加。总共获得了>10,000倍的高纯度活化NK细胞，T细胞污染可忽略不计。为了确认通过该方法扩增的NK细胞的抗肿瘤活性，在人结直肠癌细胞存在的情况下，将扩增的NK细胞与西妥昔单抗、放疗或西妥昔单抗与放疗的联合方案共同处理。扩增的NK细胞可有效靶向人结直肠癌细胞，尤其是与西妥昔单抗和放疗联合使用时。
因此，在本研究中，开发了一种利用活化和辐照的PBMCs进行高纯度活化NK细胞扩增的新方法。此外，将放疗和基于抗体的免疫治疗与扩增的NK细胞联合使用，可能是提高结直肠癌治疗效率的有效策略。
Natural killer (NK) cells play a crucial role in early immune defenses against transformed cells and are used in the therapeutic management of cancer.
However, it is difficult to sufficiently obtain high purity activated NK cells for clinical application. The function of NK cells is dependent on the balance of activating and inhibitory signals. Strong and diverse stimuli are required to increase the function of NK cells. Radiotherapy modulates the expression of various immunomodulatory molecules that recruit and activate NK cells. NK cell-mediated antibody-dependent cellular cytotoxicity is one of the most potent cytotoxic effects of NK cells against target cancer cells. To generate activated and irradiated autologous peripheral blood mononuclear cells (PBMCs), cytokine and monoclonal antibody stimulation followed by ionizing radiation was performed in the present study. The expanded NK cells were cultured for 21 days using activated/irradiated autologous PBMCs.
Colorectal cancer cells (SW480 and HT-29) were used to analyze the expression of NK group 2D ligands and EGFR by radiation. The cytotoxicity of radiation plus NK cell-based targeted therapy against colorectal cancer cell lines was analyzed using flow cytometry. Activated and irradiated PBMCs exhibited significantly increased expression of various activating ligands that stimulated NK cells.
In total, >10,000-fold high-purity activated NK cells were obtained, with negligible T-cell contamination. To confirm the antitumor activity of the NK cells expanded by this method, the expanded NK cells were treated with cetuximab, radiotherapy, or a combination of cetuximab and radiotherapy in the presence of human colorectal cancer cells. Expanded NK cells were effective at targeting human colorectal cancer cells, particularly when combined with cetuximab and radiotherapy.
Thus, in the present study, a novel method for high-purity activated NK cell expansion was developed using activated and irradiated PBMCs.
In addition, combined radiotherapy and antibody-based immunotherapy with expanded NK cells may be an effective strategy to enhance the efficiency of treatment against colorectal cancer.
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