European University of Madrid, Calle del Tajo S/N, 28670 Villaviciosa de Odón, Madrid, Spain.
Department of Clinical Analysis, University Hospital of Getafe, Carretera de Toledo, km 12,500, Getafe, Madrid, Spain.
Vaccine. 2017 Nov 7;35(47):6395-6403. doi: 10.1016/j.vaccine.2017.10.008. Epub 2017 Oct 10.
Head and neck squamous cell carcinoma (HNSCC) is one of the most frequent cancers worldwide and is associated with poor survival and significant treatment morbidity. The immune profile in patients with HNSCC is immunosuppressive and presents cytokine-mediated adaptive immune responses, triggered apoptosis of T cells, and alterations in antigen processing machinery. Bacille Calmette-Guerin (BCG) immunotherapy has been used successfully as a treatment for several types of cancer. In the present study, we sought to determine the antitumor effect of soluble mediators from peripheral blood mononuclear immune cells (PBMCs) activated with BCG vaccine in a three-dimensional coculture model of HNSCC growth using FaDu hypopharynx carcinoma squamous cells. BCG activation of PBMCs led to an increase in CD4+ and CD8+ lymphocyte subsets concomitant with an elevation in the levels of the antitumor cytokines IL-6, TNF-α and IFN-γ, and a EGFR in FaDu cells. In addition, coculture with BCG-activated PBMCs reduced FaDu proliferation and increased cytotoxicity and apoptosis in parallel with an increase in caspase-3 activity and p53 expression. Finally, conditioned medium from BCG-activated PBMCs reduced the levels of the angiogenic factors vascular endothelial growth factor and angiopoietin-2 produced by human aortic endothelial cells (HAECs), and inhibited their proliferation and differentiation into capillary-like structures. Taken together, these results demonstrate that BCG vaccination induces antitumor responses in an HNSCC in vitro model and suggest that the BCG vaccine could be an effective alternative therapy for the treatment of HNSCC.
头颈部鳞状细胞癌（HNSCC）是全球最常见的癌症之一，与生存率低和治疗相关发病率高有关。HNSCC 患者的免疫谱呈免疫抑制状态，表现为细胞因子介导的适应性免疫反应，触发 T 细胞凋亡，并改变抗原加工机制。卡介苗（BCG）免疫疗法已成功用于治疗多种癌症。在本研究中，我们试图确定用 BCG 疫苗激活外周血单个核免疫细胞（PBMC）产生的可溶性介质在使用 FaDu 下咽鳞癌细胞的 HNSCC 生长的三维共培养模型中的抗肿瘤作用。BCG 激活 PBMC 导致 CD4+和 CD8+淋巴细胞亚群增加，同时抗肿瘤细胞因子 IL-6、TNF-α 和 IFN-γ以及 FaDu 细胞中的 EGFR 水平升高。此外，与 BCG 激活的 PBMC 共培养可降低 FaDu 的增殖，并增加细胞毒性和细胞凋亡，同时 caspase-3 活性和 p53 表达增加。最后，BCG 激活的 PBMC 产生的条件培养基可降低人主动脉内皮细胞（HAEC）产生的血管内皮生长因子和血管生成素-2 的水平，并抑制其增殖和分化为毛细血管样结构。总之，这些结果表明，BCG 疫苗可在体外 HNSCC 模型中诱导抗肿瘤反应，并表明 BCG 疫苗可能是治疗 HNSCC 的有效替代疗法。
