CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：T cell receptor engineering of primary NK cells to therapeutically target tumors and tumor immune evasion.
T cell receptor engineering of primary NK cells to therapeutically target tumors and tumor immune evasion.
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NK-TCR 细胞疗法通过额外的 TCR 介导的裂解增强 NK 细胞对肿瘤的效力。此外，NK-TCR 的双重功效允许特异性靶向肿瘤及相关的 TCR 相关免疫抵抗，使 NK-TCR 成为一种独特的细胞疗法。
T细胞受体（TCR）工程化细胞可以成为治疗恶性肿瘤的强大工具。然而，人类白细胞抗原（HLA）I类下调导致的肿瘤耐药性可能对任何TCR介导的细胞疗法的成功产生负面影响。异体自然杀伤（NK）细胞已在对恶性肿瘤的治疗中展现出疗效和安全性，且不诱导移植物抗宿主病，凸显了“现货型”细胞治疗的可行性。此外，原代NK细胞可以利用多种内在激活机制靶向肿瘤。在本研究中，我们将NK细胞的抗肿瘤效应功能与TCR工程化相结合（NK-TCR），创建了一种新型治疗策略，以避免TCR相关的免疫耐药。
BOB1是一种在所有健康及恶性B细胞谱系中高表达的转录因子，包括多发性骨髓瘤（MM）。通过两步逆转录病毒转导方案，在外周血来源的NK细胞中实现了HLA-B*07:02限制性BOB1特异性TCR的表达。随后，在体外和体内将NK-TCR与TCR阴性NK细胞及表达相同TCR的CD8-T细胞进行比较，评估其对HLA-B*07:02+ B细胞来源的淋巴母细胞样细胞系（B-LCL）、B细胞急性淋巴细胞白血病和MM细胞系的效应功能。
首先，TCR 可在来自多名健康供体外周血的 NK 细胞中可重复地表达，从而生成纯化的 NK-TCR 细胞产品。其次，NK-TCR 对既往对 NK 介导的裂解具有耐药性的恶性肿瘤表现出抗原特异性效应功能，并在 MM 的临床前异种移植模型中增强了 NK 的体内疗效。此外，NK-TCR 的抗原特异性细胞毒性和细胞因子产生与表达相同 TCR 的 CD8 T 细胞相当。最后，在 HLA-I 类缺失的模型中，B2M KO 的肿瘤细胞被 NK-TCR 以 NK 介导的方式裂解，但对 T 细胞为基础的杀伤具有耐药性。
T cell receptor (TCR)-engineered cells can be powerful tools in the treatment of malignancies. However, tumor resistance by Human Leukocyte antigen (HLA) class I downregulation can negatively impact the success of any TCR-mediated cell therapy. Allogeneic natural killer (NK) cells have demonstrated efficacy and safety against malignancies without inducing graft-versus-host-disease, highlighting the feasibility for an 'off the shelf' cellular therapeutic. Furthermore, primary NK cells can target tumors using a broad array of intrinsic activation mechanisms. In this study, we combined the antitumor effector functions of NK cells with TCR engineering (NK-TCR), creating a novel therapeutic strategy to avoid TCR-associated immune resistance.
BOB1, is a transcription factor highly expressed in all healthy and malignant B cell lineages, including multiple myeloma (MM). Expression of an HLA-B*07:02 restricted BOB1-specifc TCR in peripheral blood-derived NK cells was achieved following a two-step retroviral transduction protocol. NK-TCR was then compared with TCR-negative NK cells and CD8-T cells expressing the same TCR for effector function against HLA-B*07:02+ B-cell derived lymphoblastoid cell lines (B-LCL), B-cell acute lymphoblastic leukemia and MM cell lines in vitro and in vivo.
Firstly, TCR could be reproducibly expressed in NK cells isolated from the peripheral blood of multiple healthy donors generating pure NK-TCR cell products. Secondly, NK-TCR demonstrated antigen-specific effector functions against malignancies which were previously resistant to NK-mediated lysis and enhanced NK efficacy in vivo using a preclinical xenograft model of MM. Moreover, antigen-specific cytotoxicity and cytokine production of NK-TCR was comparable to CD8 T cells expressing the same TCR. Finally, in a model of HLA-class I loss, tumor cells with B2M KO were lysed by NK-TCR in an NK-mediated manner but were resistant to T-cell based killing.
NK-TCR cell therapy enhances NK cell efficacy against tumors through additional TCR-mediated lysis. Furthermore, the dual efficacy of NK-TCR permits the specific targeting of tumors and the associated TCR-associated immune resistance, making NK-TCR a unique cellular therapeutic.
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