Blocking KCa3.1 Channels Increases Tumor Cell Killing by a Subpopulation of Human Natural Killer Lymphocytes
Blocking KCa3.1 Channels Increases Tumor Cell Killing by a Subpopulation of Human Natural Killer Lymphocytes
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DOI：
10.1371/journal.pone.0076740
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发表时间：
2013-10-11
期刊：
影响因子：
3.7
通讯作者：
Beeton, Christine
中科院分区：
文献类型：
--
作者：
Koshy, Shyny;Wu, Danli;Beeton, Christine
自然杀伤（NK）细胞是大颗粒淋巴细胞，其参与针对肿瘤和病原体的先天性和适应性免疫应答。它们还涉及其他疾病，包括器官排斥、移植物抗宿主病、复发性自然流产和自身免疫性疾病，如多发性硬化症。我们证明，人类NK细胞表达钾通道Kv1.3和KCa3.1。这些通道的表达不随成熟标志物的表达水平而变化，但在粘附和非粘附NK细胞亚群之间变化。在被有丝分裂原或肿瘤细胞激活后，粘附NK（A-NK）细胞优先上调KCa 3.1，非粘附（NA-NK）细胞优先上调Kv 1.3。与这种不同的表型一致，在功能测定中，A-NK和NA-NK对选择性KCa 3.1阻断剂TRAM-34和NS 6180以及对选择性Kv 1.3阻断剂ShK-186和PAP-1不显示相同的敏感性。Kv1.3阻断抑制NA-NK细胞的增殖和脱粒，对A-NK细胞的影响最小。相反，阻断KCa 3.1增加A-NK细胞的脱粒和细胞毒性，但不增加NA-NK细胞的脱粒和细胞毒性。然而，TRAM-34不影响它们与靶肿瘤细胞形成缀合物、迁移或表达趋化因子受体的能力。TRAM-34和NS 6180也增加A-NK和NA-NK细胞的增殖。这导致TRAM-34诱导的A-NK细胞减少体内肿瘤生长的能力增加。总而言之，我们的结果表明，使用选择性阻滞剂靶向NK细胞上的KCa3.1可能对癌症免疫治疗有益。
Natural killer (NK) cells are large granular lymphocytes that participate in both innate and adaptive immune responses against tumors and pathogens. They are also involved in other conditions, including organ rejection, graft-versus-host disease, recurrent spontaneous abortions, and autoimmune diseases such as multiple sclerosis. We demonstrate that human NK cells express the potassium channels Kv1.3 and KCa3.1. Expression of these channels does not vary with expression levels of maturation markers but varies between adherent and non-adherent NK cell subpopulations. Upon activation by mitogens or tumor cells, adherent NK (A-NK) cells preferentially up-regulate KCa3.1 and non-adherent (NA-NK) cells preferentially up-regulate Kv1.3. Consistent with this different phenotype, A-NK and NA-NK do not display the same sensitivity to the selective KCa3.1 blockers TRAM-34 and NS6180 and to the selective Kv1.3 blockers ShK-186 and PAP-1 in functional assays. Kv1.3 block inhibits the proliferation and degranulation of NA-NK cells with minimal effects on A-NK cells. In contrast, blocking KCa3.1 increases the degranulation and cytotoxicity of A-NK cells, but not of NA-NK cells. TRAM-34, however, does not affect their ability to form conjugates with target tumor cells, to migrate, or to express chemokine receptors. TRAM-34 and NS6180 also increase the proliferation of both A-NK and NA-NK cells. This results in a TRAM-34-induced increased ability of A-NK cells to reduce in vivo tumor growth. Taken together, our results suggest that targeting KCa3.1 on NK cells with selective blockers may be beneficial in cancer immunotherapy.