肿瘤细胞治疗研究
英文原题：Therapeutic Inducers of Natural Killer cell Killing (ThINKK): preclinical assessment of safety and efficacy in allogeneic hematopoietic stem cell transplant settings.
我们的结果表明，ThINKK 是产生 I 型 IFN 的细胞，其 T 细胞活化能力较低。
背景：异基因造血干细胞移植（HSCT）仍是化疗难治性白血病的标准治疗，但治愈率仍令人失望。为预防 HSCT 后白血病复发，本研究旨在增强自然杀伤（NK）细胞介导的早期移植物抗白血病效应。研究采用 NK 细胞杀伤治疗诱导细胞（ThINKK）过继转移策略。ThINKK 由造血干细胞扩增和分化而来，具有血液浆细胞样树突状细胞（pDC）特征。我们此前已证明，ThINKK 可刺激 NK 细胞，并在 ALL 的临床前 HSCT 小鼠模型中控制急性淋巴细胞白血病（ALL）进展。本研究评估 ThINKK 的细胞身份及其激活异基因 T 细胞的潜能，最后分析免疫抑制药物对 ThINKK-NK 细胞相互作用的影响。 方法：使用单细胞 RNA 测序和流式细胞术研究 ThINKK 细胞身份；在有或无 ThINKK 的情况下共培养异基因 T 细胞和抗原呈递细胞，以评估 T 细胞活化潜能；使用人源至小鼠异种移植模型评估 ThINKK 注射对移植物抗宿主病（GvHD）的影响；并测试免疫抑制药物对 ThINKK 诱导 NK 细胞杀伤 ALL 细胞的作用。 结果：绝大多数 ThINKK 具有典型血液 pDC 的关键特征，包括在 Toll 样受体刺激后强效产生 I 型干扰素（IFN）。少数亚群表达其他树突状细胞群的部分（但非全部）标志物。重要的是，ThINKK 不会被异基因 T 或 NK 细胞杀伤，也不会增加抗原呈递细胞诱导的 T 细胞增殖，或加重体内 GvHD。最后，tacrolimus、sirolimus 或 mycophenolate 均未降低 ThINKK 诱导的 NK 细胞活化和细胞毒性。 结论：ThINKK 是产生 I 型 IFN 且 T 细胞活化能力低的细胞，因此 ThINKK 过继免疫治疗预计不会增加异基因 HSCT 后 GvHD 风险。此外，数据预测 tacrolimus、sirolimus 或 mycophenolate 作为 GvHD 预防方案，不会降低 ThINKK 治疗效力。总体而言，这些临床前数据支持开展 I 期临床试验评估 ThINKK 免疫疗法。
BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) remains the standard of care for chemotherapy-refractory leukemia patients, but cure rates are still dismal. To prevent leukemia relapse following HSCT, we aim to improve the early graft-versus-leukemia effect mediated by natural killer (NK) cells. Our approach is based on the adoptive transfer of Therapeutic Inducers of Natural Killer cell Killing (ThINKK). ThINKK are expanded and differentiated from HSC, and exhibit blood plasmacytoid dendritic cell (pDC) features. We previously demonstrated that ThINKK stimulate NK cells and control acute lymphoblastic leukemia (ALL) development in a preclinical mouse model of HSCT for ALL. Here, we assessed the cellular identity of ThINKK and investigated their potential to activate allogeneic T cells. We finally evaluated the effect of immunosuppressive drugs on ThINKK-NK cell interaction. METHODS: ThINKK cellular identity was explored using single-cell RNA sequencing and flow cytometry. Their T-cell activating potential was investigated by coculture of allogeneic T cells and antigen-presenting cells in the presence or the absence of ThINKK. A preclinical human-to-mouse xenograft model was used to evaluate the impact of ThINKK injections on graft-versus-host disease (GvHD). Finally, the effect of immunosuppressive drugs on ThINKK-induced NK cell cytotoxicity against ALL cells was tested. RESULTS: The large majority of ThINKK shared the key characteristics of canonical blood pDC, including potent type-I interferon (IFN) production following Toll-like receptor stimulation. A minor subset expressed some, although not all, markers of other dendritic cell populations. Importantly, while ThINKK were not killed by allogeneic T or NK cells, they did not increase T cell proliferation induced by antigen-presenting cells nor worsened GvHD in vivo. Finally, tacrolimus, sirolimus or mycophenolate did not decrease ThINKK-induced NK cell activation and cytotoxicity. CONCLUSION: Our results indicate that ThINKK are type I IFN producing cells with low T cell activation capacity. Therefore, ThINKK adoptive immunotherapy is not expected to increase the risk of GvHD after allogeneic HSCT. Furthermore, our data predict that the use of tacrolimus, sirolimus or mycophenolate as anti-GvHD prophylaxis regimen will not decrease ThINKK therapeutic efficacy. Collectively, these preclinical data support the testing of ThINKK immunotherapy in a phase I clinical trial.
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