Biophysics, Center for Integrative Physiology and Molecular Medicine, School of Medicine, Saarland University, Homburg, 66421, Germany.
Cardiovascular Physiology, University Medical Center, University of Göttingen, Göttingen, 37073, Germany.
J Physiol. 2018 Jul;596(14):2681-2698. doi: 10.1113/JP274964. Epub 2018 Mar 12.
Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells are required to eliminate cancer cells. We analysed the Ca dependence of CTL and NK cell cytotoxicity and found that in particular CTLs have a very low optimum of [Ca ] (between 122 and 334 nm) and [Ca ] (between 23 and 625 μm) for efficient cancer cell elimination, well below blood plasma Ca levels. As predicted from these results, partial down-regulation of the Ca channel Orai1 in CTLs paradoxically increases perforin-dependent cancer cell killing. Lytic granule release at the immune synapse between CTLs and cancer cells has a Ca optimum compatible with this low Ca optimum for efficient cancer cell killing, whereas the Ca optimum for CTL migration is slightly higher and proliferation increases monotonously with increasing [Ca ] . We propose that a partial inhibition of Ca signals by specific Orai1 blockers at submaximal concentrations could contribute to tumour elimination.
Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells are required to protect the human body against cancer. Ca is a key metabolic factor for lymphocyte function and cancer homeostasis. We analysed the Ca dependence of CTL and NK cell cytotoxicity against cancer cells and found that CTLs have a bell-shaped Ca dependence with an optimum for cancer cell elimination at rather low [Ca ] (23-625 μm) and [Ca ] (122-334 nm). This finding predicts that a partial inhibition of Orai1 should increase (rather than decrease) cytotoxicity of CTLs at [Ca ] higher than 625 μm. We tested this hypothesis in CTLs and indeed found that partial down-regulation of Orai1 by siRNA increases the efficiency of cancer cell killing. We found two mechanisms that may account for the Ca optimum of cancer cell killing: (1) migration velocity and persistence have a moderate optimum between 500 and 1000 μm [Ca ] in CTLs, and (2) lytic granule release at the immune synapse between CTLs and cancer cells is increased at 146 μm compared to 3 or 800 μm, compatible with the Ca optimum for cancer cell killing. It has been demonstrated in many cancer cell types that Orai1-dependent Ca signals enhance proliferation. We propose that a decrease of [Ca ] or partial inhibition of Orai1 activity by selective blockers in the tumour microenvironment could efficiently reduce cancer growth by simultaneously increasing CTL and NK cell cytotoxicity and decreasing cancer cell proliferation.
细胞毒性 T 淋巴细胞（CTLs）和自然杀伤（NK）细胞是消除癌细胞所必需的。我们分析了 CTL 和 NK 细胞细胞毒性的钙依赖性，发现 CTL 对有效消除癌细胞的最佳钙离子浓度和钙浓度有非常低的要求（分别为 122 至 334nm 和 23 至 625μm），远低于血浆钙离子浓度。根据这些结果预测，CTL 中钙通道 Orai1 的部分下调反而会增加穿孔素依赖性癌细胞杀伤。CTL 与癌细胞之间免疫突触中的裂解颗粒释放具有与有效杀伤癌细胞相兼容的钙最佳值，而 CTL 迁移的钙最佳值略高，并且增殖随钙离子浓度的增加而单调增加。我们提出，在亚最大浓度下使用特定的 Orai1 阻断剂部分抑制钙信号可能有助于肿瘤消除。
细胞毒性 T 淋巴细胞（CTLs）和自然杀伤（NK）细胞是保护人体免受癌症侵害所必需的。钙是淋巴细胞功能和癌症动态平衡的关键代谢因素。我们分析了 CTL 和 NK 细胞对癌细胞的细胞毒性的钙依赖性，发现 CTL 具有钟形钙依赖性，对癌细胞的消除具有最佳的钙离子浓度（23-625μm）和钙浓度（122-334nm）。这一发现表明，Orai1 的部分抑制应该会增加（而不是降低）高于 625μm 钙离子浓度时 CTL 的细胞毒性。我们在 CTL 中测试了这一假设，确实发现通过 siRNA 部分下调 Orai1 会增加癌细胞杀伤的效率。我们发现两种可能解释癌细胞杀伤钙最佳值的机制：（1）CTL 中迁移速度和持久性在 500 至 1000μm[Ca]之间具有中等最佳值，（2）CTL 与癌细胞之间免疫突触处的裂解颗粒释放增加 146μm，与癌细胞杀伤的钙最佳值相比，3μm 或 800μm 增加了，与癌细胞杀伤的钙最佳值相匹配。在许多癌细胞类型中已经证明，Orai1 依赖性钙信号增强增殖。我们提出，通过降低肿瘤微环境中的[Ca]或通过选择性阻断剂部分抑制 Orai1 活性，可以通过同时增加 CTL 和 NK 细胞的细胞毒性和降低癌细胞的增殖来有效减少癌症的生长。
