Tumor-Derived Lactate Modifies Antitumor Immune Response: Effect on Myeloid-Derived Suppressor Cells and NK Cells
Tumor-Derived Lactate Modifies Antitumor Immune Response: Effect on Myeloid-Derived Suppressor Cells and NK Cells
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DOI：
10.4049/jimmunol.1202702
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发表时间：
2013-08-01
影响因子：
4.4
通讯作者：
Sukhatme, Vikas P.
中科院分区：
文献类型：
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作者：
Husain, Zaheed;Huang, Yannu;Sukhatme, Vikas P.
在这项研究中，我们探索了一种假设，即由于肿瘤细胞糖酵解活性高，从而增强了乳酸的产生，从而抑制了宿主对肿瘤细胞的免疫反应。乳酸脱氢酶a （LDH-A）负责丙酮酸转化为乳酸，在肿瘤细胞中高度表达。慢病毒载体介导的LDH-A短发夹RNA敲低的Pan02胰腺癌细胞注射到C57BL/6小鼠的肿瘤比注射Pan02细胞的小鼠小。携带ldl -A缺失肿瘤的小鼠脾脏中髓源性抑制细胞（MDSCs）的频率降低。来自ldh - a缺失肿瘤的NK细胞具有改善的细胞溶解功能。外源性乳酸增加了小鼠骨髓细胞与GM-CSF和IL-6在体外生成MDSCs的频率。乳酸预处理NK细胞对人和小鼠NK细胞的细胞溶解功能均有抑制作用。NK细胞毒性活性的降低伴随着NK细胞穿孔素和颗粒酶的表达降低。乳酸处理的NK细胞中NKp46的表达降低。这些研究强烈表明，肿瘤来源的乳酸通过直接抑制细胞溶解功能以及间接通过增加抑制NK细胞毒性的MDSCs数量来抑制NK细胞功能。使用生酮饮食降低糖酵解肿瘤的乳酸生成，降低葡萄糖水平，导致肿瘤变小，MDSC频率降低，并改善抗肿瘤免疫反应。这些研究为肿瘤来源的乳酸盐通过调节MDSC和NK细胞活性来抑制先天免疫应答的免疫抑制作用提供了证据。
In this study, we explore the hypothesis that enhanced production of lactate by tumor cells, because of high glycolytic activity, results in inhibition of host immune response to tumor cells. Lactate dehydrogenase-A (LDH-A), responsible for conversion of pyruvate to lactate, is highly expressed in tumor cells. Lentiviral vector-mediated LDH-A short hairpin RNA knockdown Pan02 pancreatic cancer cells injected in C57BL/6 mice developed smaller tumors than mice injected with Pan02 cells. A decrease occurred in the frequency of myeloid-derived suppressor cells (MDSCs) in the spleens of mice carrying LDH-A-depleted tumors. NK cells from LDH-A-depleted tumors had improved cytolytic function. Exogenous lactate increased the frequency of MDSCs generated from mouse bone marrow cells with GM-CSF and IL-6 in vitro. Lactate pretreatment of NK cells in vitro inhibited cytolytic function of both human and mouse NK cells. This reduction of NK cytotoxic activity was accompanied by lower expression of perforin and granzyme in NK cells. The expression of NKp46 was decreased in lactate-treated NK cells. These studies strongly suggest that tumor-derived lactate inhibits NK cell function via direct inhibition of cytolytic function as well as indirectly by increasing the numbers of MDSCs that inhibit NK cytotoxicity. Depletion of glucose levels using a ketogenic diet to lower lactate production by glycolytic tumors resulted in smaller tumors, decreased MDSC frequency, and improved antitumor immune response. These studies provide evidence for an immunosuppressive role of tumor-derived lactate in inhibiting innate immune response against developing tumors via regulation of MDSC and NK cell activity.