Deletion of Lactate Dehydrogenase-A in Myeloid Cells Triggers Antitumor Immunity.
Deletion of Lactate Dehydrogenase-A in Myeloid Cells Triggers Antitumor Immunity.
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DOI：
10.1158/0008-5472.can-16-2938
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发表时间：
2017-07-01
期刊：
影响因子：
11.2
通讯作者：
Wegiel B
中科院分区：
文献类型：
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作者：
Seth P;Csizmadia E;Hedblom A;Vuerich M;Xie H;Li M;Longhi MS;Wegiel B
免疫代谢正在成为癌症病理生理学的关键决定因素。在这项研究中，我们探讨了巨噬细胞表达的乳酸脱氢酶-A（LDH-A）在K-Ras小鼠肺癌模型中的肿瘤形成的贡献。骨髓特异性LDH-A缺失促进了具有CD 86高和MCP-1高M1样表型的巨噬细胞的积聚，抑制了肿瘤生长。这种表型效应伴随着VEGF表达和血管生成减少; PD-L1+癌细胞数量减少; CD 3 + T细胞数量增加和CD 8 + T细胞活化状态。此外，通过诱导产生IL-17和IFNγ的CD 8 + T（Tc 17和Tc 1）细胞，可能通过抑制乳酸盐驱动的PD-L1表达，与更显著的抗肿瘤T细胞免疫相关。我们的研究结果表明，肿瘤微环境中巨噬细胞表达LDH-A和乳酸是T细胞免疫抑制的主要驱动因素，强烈支持靶向基质LDH-A作为钝肿瘤免疫逃逸的有效策略的概念。
Immunometabolism is emerging as a critical determinant of cancer pathophysiology. In this study, we explored the contributions of macrophage-expressed lactate dehydrogenase-A (LDH-A) to tumor formation in a K-Ras murine model of lung carcinoma. Myeloid-specific deletion of LDH-A promoted accumulation of macrophages with a CD86high and MCP-1high M1-like phenotype that suppressed tumor growth. This phenotypic effect was accompanied by reduced VEGF expression and angiogenesis; diminished numbers of PD-L1+ cancer cells; increased numbers of CD3+ T cells and activation status of CD8+ T cells. Further, it was associated with more pronounced antitumor T cell immunity via induction of IL-17 and IFNγ-producing CD8+ T (Tc17 and Tc1) cells, likely via suppression of lactate-driven PD-L1 expression. Our results suggest that expression of LDH-A and lactate by macrophage in the tumor microenvironment are major drivers of T cell immunosuppression, strongly supporting the concept of targeting stromal LDH-A as an effective strategy to blunt tumoral immune escape.