Kim Ryungsa, Emi Manabu, Tanabe Kazuaki, Arihiro Koji
International Radiation Information Center, Research Institute for Radiation Biology and Medicine, Hiroshima University, Japan.
Cancer Res. 2006 Jun 1;66(11):5527-36. doi: 10.1158/0008-5472.CAN-05-4128.
Tumors evolve mechanisms to escape immune control by a process called immune editing, which provides a selective pressure in the tumor microenvironment that could lead to malignant progression. A variety of tumor-derived factors contribute to the emergence of complex local and regional immunosuppressive networks, including vascular endothelial growth factor, interleukin-10, transforming growth factor-beta, prostaglandin E(2), and soluble phosphatidylserine, soluble Fas, soluble Fas ligand, and soluble MHC class I-related chain A proteins. Although deposited at the primary tumor site, these secreted factors could extend immunosuppressive effects into the local lymph nodes and the spleen, promoting invasion and metastasis. Vascular endothelial growth factors play a key role in recruiting immature myeloid cells from the bone marrow to enrich the microenvironment as tumor-associated immature dendritic cells and tumor-associated macrophages. The understanding of the immunosuppressive networks that evolve is incomplete, but several features are emerging. Accumulation of tumor-associated immature dendritic cells may cause roving dendritic cells and T cells to become suppressed by the activation of indoleamine 2,3-dioxygenase and arginase I by tumor-derived growth factors. Soluble phosphatidylserines support tumor-associated macrophages by stimulating the release of anti-inflammatory mediators that block antitumor immune responses. Soluble Fas, soluble FasL, and soluble MHC class I-related chain A proteins may help tumor cells escape cytolysis by cytotoxic T cells and natural killer cells, possibly by counterattacking immune cells and causing their death. In summary, tumor-derived factors drive the evolution of an immunosuppressive network which ultimately extends immune evasion from the primary tumor site to peripheral sites in patients with cancer.
肿瘤通过一种称为免疫编辑的过程进化出逃避免疫控制的机制，这在肿瘤微环境中产生了一种选择性压力，可能导致恶性进展。多种肿瘤衍生因子促成了复杂的局部和区域免疫抑制网络的出现，包括血管内皮生长因子、白细胞介素-10、转化生长因子-β、前列腺素E(2)，以及可溶性磷脂酰丝氨酸、可溶性Fas、可溶性Fas配体和可溶性MHC I类相关链A蛋白。尽管这些分泌因子沉积在原发性肿瘤部位，但它们可将免疫抑制作用扩展至局部淋巴结和脾脏，促进侵袭和转移。血管内皮生长因子在从骨髓募集未成熟髓样细胞以充实微环境方面起关键作用，这些细胞可成为肿瘤相关未成熟树突状细胞和肿瘤相关巨噬细胞。目前对所形成的免疫抑制网络的理解尚不完整，但一些特征正在显现。肿瘤相关未成熟树突状细胞的积累可能导致游走树突状细胞和T细胞被肿瘤衍生生长因子激活的吲哚胺2,3-双加氧酶和精氨酸酶I抑制。可溶性磷脂酰丝氨酸通过刺激释放阻断抗肿瘤免疫反应的抗炎介质来支持肿瘤相关巨噬细胞。可溶性Fas、可溶性FasL和可溶性MHC I类相关链A蛋白可能有助于肿瘤细胞逃避细胞毒性T细胞和自然杀伤细胞的细胞溶解作用，可能是通过反击免疫细胞并导致其死亡。总之，肿瘤衍生因子驱动免疫抑制网络的进化，最终将免疫逃逸从原发性肿瘤部位扩展至癌症患者的外周部位。
