Vitamin D Plus Celecoxib Therapy to Stimulate Intratumoral Immune Reactivity

口腔鳞状细胞癌（OSCC）是一种侵袭性恶性肿瘤，生存期为5年， 在过去的30年里，口腔鳞状细胞癌患者的免疫治疗方法可能是替代方案 治疗。不幸的是，OSCC患者存在由肿瘤诱导的免疫缺陷介导的严重免疫缺陷， 抑制细胞，包括肿瘤动员的CD34+祖细胞和Treg。我们过去的体外研究和我们 正在进行的VA择优审查试验显示，1，25-二羟维生素D3 [1，25（OH）2D3]诱导分化， 将免疫抑制性CD34+祖细胞转化为免疫刺激性树突细胞。然而，我们最近 还表明，OSCC诱导内皮细胞成为免疫抑制通过刺激他们产生， 免疫抑制介质PGE 2，其反过来诱导它们产生抑制介质 IL-6。PGE2和IL-6都刺激其他抑制性细胞类型，如M2巨噬细胞和Treg细胞。 这项研究的假设是，OSCC肿瘤中的有益T细胞反应性可以通过以下方式协同刺激： 阻断抑制性内皮细胞及其诱导其他抑制性细胞群，同时也使其成熟 将免疫抑制性CD34+细胞转化为抗原呈递树突细胞。 为了验证这一假设，新诊断的口腔鳞癌患者将被给予考克斯-2抑制剂塞来昔布 和/或1，25（OH）2D3，持续癌症诊断和手术治疗之间的3周时间。以下 目的是测试联合治疗的免疫学和临床有效性： #1阻断内皮细胞的抑制活性并增加刺激性树突状细胞的水平 T细胞反应性，从而协同增加肿瘤内T细胞反应性。这些功能 免疫分析将使用从未经治疗的患者或用以下方法治疗的患者中取出的OSCC组织 塞来昔布和/或1，25（OH）2D3。 #2：通过协同刺激肿瘤内T细胞反应性来减少OSCC复发的发展 塞来昔布阻断抑制性内皮细胞活性，1，25（OH）2D3使CD34+抑制因子成熟 细胞转化为T细胞刺激性树突细胞。 这些研究的长期应用是使用阻断免疫抑制细胞的治疗， 与靶向OSCC的T细胞活化疫苗一起增强树突状细胞成熟。的结果予以 研究将适用于诱导免疫抑制细胞的其他类型的恶性肿瘤，包括肺 和前列腺癌，这是越来越突出的老龄化退伍军人人口。

Oral squamous cell carcinoma (OSCC) is an aggressive malignancy with a 5 year survival that has remained at 50% for the last 30 years. Immunotherapeutic approaches for OSCC patients may be alternative treatments. Unfortunately, OSCC patients have profound immune defects mediated by tumor-induced immune suppressor cells including tumor-mobilized CD34+ progenitor cells and Treg. Our past in vitro studies and our ongoing VA merit-review trial are showing that 1¿,25-dihydroxyvitamin D3 [1,25(OH)2D3] induces differentiation of immune suppressive CD34+ progenitor cells into immune stimulatory dendritic cells. However, we recently also showed that OSCC induce endothelial cells to become immune inhibitory by stimulating them to produce the immune suppressive mediator PGE2 which, in turn, induces their production of the suppressive mediator IL-6. Both PGE2 and IL-6 stimulate other suppressive cell types such as M2 macrophages and Treg cells. The hypothesis of this study is beneficial T-cell reactivity in OSCC tumors can be synergistically stimulated by blocking suppressor endothelial cells and their induction of other inhibitory cell populations while also maturing immune inhibitory CD34+ cells into antigen-presenting dendritic cells. To test this hypothesis, newly diagnosed OSCC patients will be administered the COX-2 inhibitor celecoxib and/or 1,25(OH)2D3 for the 3 week duration between cancer diagnosis and surgical treatment. The following aims will test the immunological and clinical effectiveness of the combination treatment: #1 To block the suppressive activity of endothelial cells and increase the levels of dendritic that are stimulatory to T-cell reactivity, thereby synergistically increasing intratumoral T-cell reactivity. These functional immune analyses will use OSCC tissues removed from untreated patients or patients treated with celecoxib and/or 1,25(OH)2D3. #2: To reduce development of OSCC recurrences by synergistically stimulating intratumoral T-cell reactivity with celecoxib to block suppressor endothelial cell activity and 1,25(OH)2D3 to mature CD34+ suppressor cells into T-cell stimulatory dendritic cells. The long-term application of these studies is to use treatments that block immune suppressor cells and enhance dendritic cell maturation together with T-cell activation vaccines targeting OSCC. The results of these studies will be applicable to other types of malignancies that induce immune suppressive cells, including lung and prostate cancer, which are increasing in prominence in the aging Veterans population.