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
结直肠癌肝转移中一部分 CD8+ T 细胞作为组织驻留记忆 T 细胞优先重建自体患者来源异种移植瘤
英文原题：A Fraction of CD8+ T Cells from Colorectal Liver Metastases Preferentially Repopulate Autologous Patient-Derived Xenograft Tumors as Tissue-Resident Memory T Cells.
查看英文原题
A Fraction of CD8+ T Cells from Colorectal Liver Metastases Preferentially Repopulate Autologous Patient-Derived Xenograft Tumors as Tissue-Resident Memory T Cells.
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中文摘要
人肝脏T细胞的多样性可能反映结直肠癌肝转移（CRLM）中的TIL组成。研究者对CRLM及邻近肝组织进行体外表征，发现CD103+CD39+CD8+组织驻留记忆T（TRM）细胞主要存在于CRLM中，因此开展进一步研究。这些TRM细胞在体外可对相应抗原产生应答。由于自体TIL的功能活性是实现个体化癌症治疗的关键，研究者采用患者来源异种移植（PDX）模型，在体内监测TIL控制CRLM来源肿瘤的能力。研究为两名患者建立CRLM PDX小鼠模型，并在体外扩增相应TIL后发现，CD4+与CD8+ TIL比例呈相反变化。这些CRLM还带有KRAS突变，因此可采用曲美替尼抑制MEK。无论TIL亚群比例如何，只有在曲美替尼治疗后，转输TIL才能对体积有限的CRLM来源肿瘤产生持续或暂时控制。
值得注意的是，部分转输TIL表现为CD103+CD8+ TRM细胞，且严格聚集在自体CRLM来源肿瘤内，而非脾脏或血液中。
因此，相较邻近肝组织，CRLM中CD103+CD39+CD8+ TRM细胞占优势，以及CD103+CD8+ TRM细胞重新定植自体肿瘤的倾向，可能使这些TIL成为治疗晚期结直肠癌的策略性靶点。
展开英文摘要原文
The diversity of T cells in the human liver may reflect the composition of TILs in CRLM.
Our ex vivo characterization of CRLM vs. adjacent liver tissue detected CD103+CD39+CD8+ T RM cells predominantly in CRLM, which prompted further assessments. These T RM cells responded to cognate antigens in vitro. As functional activities of autologous TILs are central to the implementation of personalized cancer treatments, we applied a patient-derived xenograft (PDX) model to monitor TILs' capacity to control CRLM-derived tumors in vivo.
We established PDX mice with CRLMs from two patients, and in vitro expansion of their respective TILs resulted in opposing CD4+ vs. CD8+ TIL ratios. These CRLMs also displayed mutated KRAS , which enabled trametinib-mediated inhibition of MEK.
Regardless of the TIL subset ratio, persistent or transient control of CRLM-derived tumors of limited size by the transferred TILs was observed only after trametinib treatment. Of note, a portion of transferred TILs was observed as CD103+CD8+ T RM cells that strictly accumulated within the autologous CRLM-derived tumor rather than in the spleen or blood.
Thus, the predominance of CD103+CD39+CD8+ T RM cells in CRLM relative to the adjacent liver and the propensity of CD103+CD8+ T RM cells to repopulate the autologous tumor may identify these TILs as strategic targets for therapies against advanced CRC.
论文信息
- 作者
- Liang F、Nilsson LM、Byvald F、Rezapour A、Taflin H、Nilsson JA、Yrlid U
- 单位
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden.Sweden
- 期刊
- Cancers2022 Jun 10
- 原文标识
- PubMed 35740548 · DOI 10.3390/cancers14122882
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