LIGHT Elevation Enhances Immune Eradication of Colon Cancer Metastases.
LIGHT Elevation Enhances Immune Eradication of Colon Cancer Metastases.
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DOI：
10.1158/0008-5472.can-16-1655
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发表时间：
2017-04-15
期刊：
影响因子：
11.2
通讯作者：
Maker AV
中科院分区：
文献类型：
--
作者：
Qiao G;Qin J;Kunda N;Calata JF;Mahmud DL;Gann P;Fu YX;Rosenberg SA;Prabhakar BS;Maker AV
大多数结肠癌患者将发展为晚期疾病，肝脏是转移性疾病的最常见部位。原发性结肠肿瘤和肝转移瘤中肿瘤浸润淋巴细胞数量增加的患者的预后有所改善。然而，在这种情况下，能够增强抗肿瘤免疫应答的分子因子仍有待阐明。我们报道了结肠癌转移微环境中的免疫刺激性细胞因子LIGHT（TNFSF14）与改善患者生存率相关，在此，我们在免疫活性小鼠模型中证明了表达LIGHT的结肠肿瘤刺激淋巴细胞增殖和肿瘤细胞特异性抗肿瘤免疫应答。在该模型中，在原发性肿瘤或肝转移灶的微环境中增加LIGHT表达触发了已建立的肿瘤的消退，并减缓了肝转移灶的生长，这是由细胞毒性T淋巴细胞介导的抗肿瘤免疫驱动的。这些反应与肿瘤浸润淋巴细胞的显著增加和转移性肿瘤中淋巴细胞归巢信号的表达增加相对应。此外，我们证明了持久的肿瘤特异性抗肿瘤免疫的证据。总之，增加LIGHT表达增加了T细胞增殖、活化和浸润，导致原发性肿瘤和结直肠肝转移中肿瘤特异性免疫介导的肿瘤消退增强。在结肠癌微环境中增加LIGHT的机制值得进一步研究，并有望成为免疫策略。
The majority of colon cancer patients will develop advanced disease with the liver being the most common site of metastatic disease. Patients with increased numbers of tumor-infiltrating lymphocytes in primary colon tumors and liver metastases have improved outcomes. However, the molecular factors which could empower anti-tumor immune responses in this setting remained to be elucidated. We reported that the immunostimulatory cytokine LIGHT (TNFSF14) in the microenvironment of colon cancer metastases associates with improved patient survival, and here we demonstrate in an immunocompetent murine model that colon tumors expressing LIGHT stimulate lymphocyte proliferation and tumor-cell specific anti-tumor immune responses. In this model, increasing LIGHT expression in the microenvironment of either primary tumors or liver metastases triggered regression of established tumors and slowed the growth of liver metastases, driven by cytotoxic T-lymphocyte mediated anti-tumor immunity. These responses corresponded with significant increases in tumor-infiltrating lymphocytes and increased expression of lymphocyte-homing signals in the metastatic tumors. Further, we demonstrated evidence of durable tumor-specific anti-tumor immunity. In conclusion, increasing LIGHT expression increased T-cell proliferation, activation, and infiltration, resulting in enhanced tumor-specific immune-mediated tumor regressions in primary tumors and colorectal liver metastases. Mechanisms to increase LIGHT in the colon cancer microenvironment warrant further investigation and hold promise as an immunotherapeutic strategy.