Vascular Biology and Angiogenesis Laboratory, Science and Technology Pole (PST), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy.
Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy.
FASEB J. 2018 Oct;32(10):5365-5377. doi: 10.1096/fj.201701103R. Epub 2018 May 15.
NK cells are effector lymphocytes involved in tumor immunosurveillance; however, in patients with solid malignancies, NK cells have compromised functions. We have previously reported that lung tumor-associated NK cells (TANKs; peripheral blood) and tumor-infiltrating NK cells (TINKs) show proangiogenic, decidual NK-like (dNK) phenotype. In this study, we functionally and molecularly investigated TINKs and TANKs from blood and tissue samples of patients with colorectal cancer (CRC), a neoplasm in which inflammation and angiogenesis have clinical relevance, and compared them to NK cells from controls and patients with nononcologic inflammatory bowel disease. CRC TINKs/TANKs showed decreased expression for the activatory marker NKG2D, impaired degranulation activity, a decidual-like NK polarization toward the CD56CD16CD9CD49 subset. TINKs and TANKs secreted cytokines with proangiogenic activities, and induce endothelial cell proliferation, migration, adhesion, and the formation of capillary-like structures in vitro. dNK cells release specific proangiogenic factors; among which, angiogenin and invasion-associated enzymes related to the MMP9-TIMP1/2 axis. Here, we describe, for the first time, to our knowledge, the expression of angiogenin, MMP2/9, and TIMP by TANKs in patients with CRC. This phenotype could be relevant to the invasive capabilities and proangiogenic functions of CRC-NK cells and become a novel biomarker. STAT3/STAT5 activation was observed in CRC-TANKs, and treatment with pimozide, a STAT5 inhibitor, reduced endothelial cell capability to form capillary-like networks, inhibiting VEGF and angiogenin production without affecting the levels of TIMP1, TIMP2, and MMP9, indicating that STAT5 is involved in cytokine modulation but not invasion-associated molecules. Combination of Stat5 or MMP inhibitors with immunotherapy could help repolarize CRC TINKs and TANKs to anti-tumor antimetastatic ones.-Bruno, A., Bassani, B., D'Urso, D. G., Pitaku, I., Cassinotti, E., Pelosi, G., Boni, L., Dominioni, L., Noonan, D. M., Mortara, L., Albini, A. Angiogenin and the MMP9-TIMP2 axis are up-regulated in proangiogenic, decidual NK-like cells from patients with colorectal cancer.
NK 细胞是参与肿瘤免疫监视的效应淋巴细胞；然而，在实体恶性肿瘤患者中，NK 细胞的功能受损。我们之前报道过，肺肿瘤相关 NK 细胞（TANKs；外周血）和肿瘤浸润 NK 细胞（TINKs）表现出促血管生成、蜕膜 NK 样（dNK）表型。在这项研究中，我们从结直肠癌（CRC）患者的血液和组织样本中对 TINKs 和 TANKs 进行了功能和分子研究，CRC 是一种具有炎症和血管生成临床相关性的肿瘤，并将其与对照者和非肿瘤炎症性肠病患者的 NK 细胞进行了比较。CRC TINKs/TANKs 表现出活化标志物 NKG2D 的表达减少、脱颗粒活性受损、向 CD56CD16CD9CD49 亚群的蜕膜 NK 极化。TINKs 和 TANKs 分泌具有促血管生成活性的细胞因子，并在体外诱导内皮细胞增殖、迁移、黏附和毛细血管样结构的形成。dNK 细胞释放特定的促血管生成因子；其中，血管生成素和与 MMP9-TIMP1/2 轴相关的侵袭相关酶。在这里，我们首次描述了，据我们所知，CRC 患者 TANKs 中血管生成素、MMP2/9 和 TIMP 的表达。这种表型可能与 CRC-NK 细胞的侵袭能力和促血管生成功能有关，并成为一种新的生物标志物。在 CRC-TANKs 中观察到 STAT3/STAT5 的激活，用 STAT5 抑制剂匹莫齐德治疗可降低内皮细胞形成毛细血管样网络的能力，抑制 VEGF 和血管生成素的产生，而不影响 TIMP1、TIMP2 和 MMP9 的水平，表明 STAT5 参与细胞因子的调节，但不参与侵袭相关分子。将 Stat5 或 MMP 抑制剂与免疫疗法联合使用，可能有助于将 CRC TINKs 和 TANKs 重新极化为抗肿瘤、抗转移的细胞。-Bruno，A.，Bassani，B.，D'Urso，D. G.，Pitaku，I.，Cassinotti，E.，Pelosi，G.，Boni，L.，Dominioni，L.，Noonan，D. M.，Mortara，L.，Albini，A. 血管生成素和 MMP9-TIMP2 轴在源自结直肠癌患者的促血管生成、蜕膜 NK 样细胞中上调。
