RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
实验性 MHC 全相合同种异体 HSCT 中采用 PTCy 或 Treg 扩增供者后 NK 细胞恢复改善
英文原题：Improved NK Cell Recovery Following Use of PTCy or Treg Expanded Donors in Experimental MHC-Matched Allogeneic HSCT.
查看英文原题
Improved NK Cell Recovery Following Use of PTCy or Treg Expanded Donors in Experimental MHC-Matched Allogeneic HSCT.
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中文摘要
异基因造血干细胞移植（allo-HSCT）会因移植物抗宿主病（GVHD）而复杂化，GVHD 通过影响初级和次级淋巴器官导致免疫功能障碍，并进一步延迟免疫重建。需要预防 GVHD 并改善 allo-HSCT 后免疫恢复的治疗方法。移植后环磷酰胺（PTCy）是一种成熟且临床广泛使用的方法，用于 HLA 相合以及单倍体相合 allo-HSCT 后的 GVHD 预防，也是错配无关供者 allo-HSCT 中一种有前景的策略。近年来，调节性 T 细胞（Tregs）作为免疫稳态和耐受诱导的关键亚群，已在实验模型和临床试验中被评估用于 GVHD 预防。自然杀伤（NK）细胞是 allo-HSCT 后最早重建的淋巴群体之一，是对抗病原体保护性免疫的重要介质，并且对于限制移植后血液系统恶性肿瘤复发也至关重要。若干报道指出，在实验性小鼠 allo-HSCT 后以及临床 allo-HSCT 后，可能发生 NK 细胞恢复延迟。
在此，我们研究了在实验性 MHC 相合 allo-HSCT 中，2 种治疗策略，PTCy 和供者扩增 Tregs（TrED），如何影响 NK 恢复。
我们的实验显示，与未治疗的 allo-HSCT 受者相比，两种策略均在 allo-HSCT 后早期（1 个月）改善 NK 细胞数量，其中 PTCy 略优于 TrED。
重要的是，与对照 allo-HSCT 受者相比，使用 PTCy 或 TrED 均改善了 NK 细胞 IFN- 产生和细胞毒功能，这由 CD107 表达以及对 NK 敏感肿瘤细胞的体内杀伤所反映。
总之，两种预防性治疗均被发现在MHC匹配、次要抗原不匹配的实验性allo-HSCT后对NK恢复和NK细胞功能有益。改善的NK恢复有助于为这些移植受者提供针对肿瘤和病原体的早期免疫。
展开英文摘要原文
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is complicated by graft- versus-host disease (GVHD), which causes immune dysfunction and further delays immune reconstitution through its effects on primary and secondary lymphoid organs. Treatments to prevent GVHD and improve immune recovery following allo-HSCT are needed. Post-transplantation cyclophosphamide (PTCy) is a well-established and clinically widely used method for GVHD prophylaxis after HLA-matched as well as haploidentical allo-HSCT, as well as a promising strategy in the setting of mismatched unrelated donor allo-HSCT.
Recently, regulatory T cells (Tregs), a critical subset for immune homeostasis and tolerance induction, have been evaluated for use as GVHD prophylaxis in experimental models and clinical trials.
Natural killer (NK) cells are one of the first lymphoid populations to reconstitute following allo-HSCT and are important mediators of protective immunity against pathogens, and are also critical for limiting post-transplantation relapse of hematologic cancers. Several reports have noted that a delay in NK cell recovery may occur following experimental mouse allo-HSCT as well as after clinical allo-HSCT.
Here we examined how 2 treatment strategies, PTCy and donor expanded Tregs (TrED), in experimental MHC-matched allo-HSCT affect NK recovery.
Our experiments show that both strategies improved NK cell numbers, with PTCy slightly better than TrED, early after allo-HSCT (1 month) compared with untreated allo-HSCT recipients.
Importantly, NK cell IFN- production and cytotoxic function, as reflected by CD107 expression as well as in vivo killing of NK-sensitive tumor cells, were improved using either PTCy or TrED versus control allo-HSCT recipients.
In conclusion, both prophylactic treatments were found to be beneficial for NK recovery and NK cell function following MHC-matched minor antigen-mismatched experimental allo-HSCT. Improved NK recovery could help provide early immunity toward tumors and pathogens in these transplant recipients.
论文信息
- 作者
- Wolf D、Barreras H、Copsel SN、Komanduri KV、Levy RB
- 单位
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida; Division of Transplantation and Cellular Therapy, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida. Electronic address: dwolf@med.miami.edu.
- 文献类型
- 非美国政府资助研究 · 美国 NIH 资助研究
- 期刊
- Transplantation and cellular therapy2022 Jun
- 原文标识
- PubMed 35302008 · DOI 10.1016/j.jtct.2022.03.012
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