“助推”杀手T细胞,增强实体瘤的免疫治疗效果 | Science子刊
2018/04/27
细胞毒性T细胞浸润实体肿瘤的能力有限,让免疫系统的免疫监视和免疫疗法对癌症的疗效“大打折扣”。现在,来自辛辛那提大学(UC)的研究揭示了帮助CD8+ T细胞浸润某些实体肿瘤的潜在新靶点。


Breast Tumor Microenvironment. Credit: Joseph Szulczewski, David Inman, Kevin Eliceiri, and Patricia Keely. NCI/ Carbone Cancer Center at the Univ. of Wisconsin

这项研究以 “A defect in KCa3.1 channel activity limits the ability of CD8+ T cells from cancer patients to infiltrate an adenosine-rich microenvironment”为题在线发表在4月24日的《Science Signaling》杂志上。

CD8+T细胞是一种能够杀死癌细胞的T细胞。最新研究表明,瞄准kca3.1钾通道,可以恢复患者样本中CD8+ T细胞的迁移,从而有望助力T细胞进入肿瘤并消灭它们。这意味着它们可能更有效地进入肿瘤并攻击它。

“抑制钾通道的活动限制了肿瘤内的T细胞运动,” 美国加州大学医学院内科系教授Laura Conforti博士说,她是辛辛那提癌症中心和UC癌症研究所的研究员,也是该研究的通讯作者。她表示,实体肿瘤内的T细胞浸润受到肿瘤微环境中多种因素的限制,其中包括腺苷,它在实体瘤中累积并抑制肿瘤特异性T细胞。

Conforti团队分析了CD8 + T细胞在3D实验模型系统(可以复制肿瘤微环境的某些特征)中的迁移过程,发现腺苷酸存在时,它可以抑制来自癌症患者T细胞的运动,而不是来自健康捐赠者的T细胞。

她说:“患者CD8+ T细胞对腺苷的敏感性增加,与KCa3.1通道活性降低有关,但与腺苷受体的表达或信号传递无关。使用一种恢复KCa3.1通道活性的物质,可以纠正腺苷存在下患者CD8+ T细胞的迁移,这表明钾通道激活剂可能有助于增强富含腺苷的实体瘤的T细胞浸润,从而提供了另一种治疗选择。”

Conforti 表示,这一发现可能会有助于开发新的治疗药物,并结合已批准的免疫制剂治疗实体肿瘤,因为它们可以提高疗效。

责编:浮苏

参考资料

Research shows possible new target for immunotherapy for solid tumors

所有文章仅代表作者观点,不代表本站立场。如若转载请联系原作者。
查看更多
  • A defect in KCa3.1 channel activity limits the ability of CD8+ T cells from cancer patients to infiltrate an adenosine-rich microenvironment

    The limited ability of cytotoxic T cells to infiltrate solid tumors hampers immune surveillance and the efficacy of immunotherapies in cancer. Adenosine accumulates in solid tumors and inhibits tumor-specific T cells. Adenosine inhibits T cell motility through the A2A receptor (A2AR) and suppression of KCa3.1 channels. We conducted three-dimensional chemotaxis experiments to elucidate the effect of adenosine on the migration of peripheral blood CD8+ T cells from head and neck squamous cell carcinoma (HNSCC) patients. The chemotaxis of HNSCC CD8+ T cells was reduced in the presence of adenosine, and the effect was greater on HNSCC CD8+ T cells than on healthy donor (HD) CD8+ T cells. This response correlated with the inability of CD8+ T cells to infiltrate tumors. The effect of adenosine was mimicked by an A2AR agonist and prevented by an A2AR antagonist. We found no differences in A2AR expression, 3′,5′-cyclic adenosine monophosphate abundance, or protein kinase A type 1 activity between HNSCC and HD CD8+ T cells. We instead detected a decrease in KCa3.1 channel activity, but not expression, in HNSCC CD8+ T cells. Activation of KCa3.1 channels by 1-EBIO restored the ability of HNSCC CD8+ T cells to chemotax in the presence of adenosine. Our data highlight the mechanism underlying the increased sensitivity of HNSCC CD8+ T cells to adenosine and the potential therapeutic benefit of KCa3.1 channel activators, which could increase infiltration of these T cells into tumors.

    展开 收起
发表评论 我在frontend\modules\comment\widgets\views\文件夹下面 test