IL-15 Overcomes Hepatocellular Carcinoma-Induced NK Cell Dysfunction.
IL-15 Overcomes Hepatocellular Carcinoma-Induced NK Cell Dysfunction.
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DOI：
10.3389/fimmu.2018.01009
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发表时间：
2018
影响因子：
7.3
通讯作者：
Maini MK
中科院分区：
文献类型：
--
作者：
Easom NJW;Stegmann KA;Swadling L;Pallett LJ;Burton AR;Odera D;Schmidt N;Huang WC;Fusai G;Davidson B;Maini MK
NK细胞具有强大的抗肿瘤能力。它们在人类肝脏中富集，其中很大一部分专门用于组织驻留。尚未研究肝脏驻留NK细胞与肝脏浸润NK细胞在人类肝脏肿瘤中增殖和发挥抗肿瘤功能的潜力。我们检测了直接从人肝细胞癌（HCC）和肝结直肠癌（CRC）转移灶中离体的肝驻留和肝浸润NK细胞，并与匹配的未受累肝组织进行比较。我们发现NK细胞在HCC和肝CRC转移中高度流行，尽管频率低于未受影响的肝脏。高达79%的肿瘤内NK细胞具有CXCR 6 + CD 69+肝脏驻留表型。直接离体染色显示，与非驻留NK细胞相比，肝脏驻留NK细胞的NKG 2D表达增加，但与未受累肝脏相比，两个亚群在肝脏肿瘤中的NKG 2D表达下调。在NKG 2D下调最显著的患者中，肿瘤内NK细胞（由Ki 67鉴定）的增殖选择性受损。人肝肿瘤NK细胞功能受损，细胞毒性和细胞因子产生能力降低，即使与未受影响的肝脏中的功能低下的组织驻留NK细胞相比。人肝NK细胞与人肝癌细胞系PLC/PRF/5或与自体HCC的共培养，概括了从肿瘤中提取的NK细胞中观察到的缺陷，NKG 2D、细胞因子产生和靶细胞毒性下调。transwell和条件培养基证实了细胞与PLC/PRF/5接触以施加NK细胞抑制的需要。IL-15能够恢复通过体外暴露于HCC细胞系或直接从HCC提取而抑制的NK细胞中的抗肿瘤功能。总之，我们的数据表明，局部NK细胞的抗肿瘤功能受损反映了肝脏驻留NK细胞固有的致耐受性特征与HCC本身施加的额外接触依赖性抑制的组合。IL-15可以在肿瘤暴露后恢复肝脏NK细胞功能的证明支持其纳入免疫治疗策略。
NK cells have potent antitumor capacity. They are enriched in the human liver, with a large subset specialized for tissue-residence. The potential for liver-resident versus liver-infiltrating NK cells to populate, and exert antitumor functions in, human liver tumors has not been studied. We examined liver-resident and liver-infiltrating NK cells directly ex vivo from human hepatocellular carcinomas (HCCs) and liver colorectal (CRC) metastases, compared with matched uninvolved liver tissue. We found that NK cells were highly prevalent in both HCC and liver CRC metastases, although at lower frequencies than unaffected liver. Up to 79% of intratumoral NK cells had the CXCR6+CD69+ liver-resident phenotype. Direct ex vivo staining showed that liver-resident NK cells had increased NKG2D expression compared to their non-resident counterparts, but both subsets had NKG2D downregulation within liver tumors compared to uninvolved liver. Proliferation of intratumoral NK cells (identified by Ki67) was selectively impaired in those with the most marked NKG2D downregulation. Human liver tumor NK cells were functionally impaired, with reduced capacity for cytotoxicity and production of cytokines, even when compared to the hypo-functional tissue-resident NK cells in unaffected liver. Coculture of human liver NK cells with the human hepatoma cell line PLC/PRF/5, or with autologous HCC, recapitulated the defects observed in NK cells extracted from tumors, with downmodulation of NKG2D, cytokine production, and target cell cytotoxicity. Transwells and conditioned media confirmed a requirement for cell contact with PLC/PRF/5 to impose NK cell inhibition. IL-15 was able to recover antitumor functionality in NK cells inhibited by in vitro exposure to HCC cell lines or extracted directly from HCC. In summary, our data suggest that the impaired antitumor function of local NK cells reflects a combination of the tolerogenic features inherent to liver-resident NK cells together with additional contact-dependent inhibition imposed by HCC itself. The demonstration that IL-15 can recover hepatic NK cell function following tumor exposure supports its inclusion in immunotherapy strategies.
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影响因子：
64.5
作者：
Fan X;Rudensky AY
通讯作者：
Rudensky AY
影响因子：
15.9
作者：
Mamessier, Emilie;Sylvain, Aude;Olive, Daniel
通讯作者：
Olive, Daniel
影响因子：
4.4
作者：
Djenidi, Faycal;Adam, Julien;Mami-Chouaib, Fathia
通讯作者：
Mami-Chouaib, Fathia
影响因子：
12.8
作者：
Hudspeth K;Donadon M;Cimino M;Pontarini E;Tentorio P;Preti M;Hong M;Bertoletti A;Bicciato S;Invernizzi P;Lugli E;Torzilli G;Gershwin ME;Mavilio D
通讯作者：
Mavilio D
影响因子：
10.1
作者：
Kamiya, Takahiro;Chang, Yu-Hsiang;Campana, Dario
通讯作者：
Campana, Dario