All-trans-retinoic acid improves differentiation of myeloid cells and immune response in cancer patients
All-trans-retinoic acid improves differentiation of myeloid cells and immune response in cancer patients
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DOI：
10.1158/0008-5472.can-06-1690
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发表时间：
2006-09-15
期刊：
影响因子：
11.2
通讯作者：
Gabrilovich, Dmitry I.
中科院分区：
文献类型：
--
作者：
Mirza, Noweeda;Fishman, Mayer;Gabrilovich, Dmitry I.
树突状细胞的异常分化和未成熟髓样抑制细胞（ImC）的积聚是肿瘤逃逸的主要机制之一。我们测试了使用全反式维甲酸（ATRA）的髓系细胞分化的药理学调节的可能性。18例转移性肾细胞癌患者接受ATIRA治疗，随后进行s.c.白细胞介素2（IL-2）。8名健康人组成对照组。正如预期的那样，癌症患者的ImC水平显著升高。我们观察到，ATRA显着减少了IMC的数量。仅在ATRA血药浓度高（> 150 ng/mL）的患者中观察到这种效应，而在ATRA血药浓度低（< 135 ng/mL）的患者中未观察到这种效应。ATRA对不同树突状细胞群比例的影响较小。然而，全反式维甲酸显着提高髓样/淋巴树突状细胞的比例和患者的单核细胞刺激同种异体T细胞的能力。这种作用与破伤风毒素特异性T细胞应答的显著改善相关。在IL-2治疗期间，ATRA效应被完全消除。为了评估IL-2的作用，分析了来自15名仅用IL-2静脉内治疗的转移性肾细胞癌患者的标本。在该组中，IL-2也显著降低了树突状细胞的数量和功能以及T细胞功能。这些数据表明有效浓度的ATRA消除了ImC，改善了骨髓/淋巴树突细胞比率、树突细胞功能和抗原特异性T细胞应答。ATHA治疗没有导致显著的毒性，并且可以在与癌症疫苗的治疗组合中进行测试。
Abnormal dendritic cell differentiation and accumulation of immature myeloid suppressor cells (ImC) is one of the major mechanisms of tumor escape. We tested the possibility of pharmacologic regulation of myeloid cell differentiation using all-trans-retinoic acid (ATRA). Eighteen patients with metastatic renal cell carcinoma were treated with ATIRA followed by s.c. interleukin 2 (IL-2). Eight healthy individuals comprised a control group. As expected, the cancer patients had substantially elevated levels of ImC. We observed that ATRA dramatically reduced the number of ImC. This effect was observed only in patients with high plasma concentration of ATRA (> 150 ng/mL), but not in patients with lower ATRA concentrations (< 135 ng/mL). Effects of ATRA on the proportions of different dendritic cell populations were minor. However, ATRA significantly improved mycloid/ lymphoid dendritic cell ratio and the ability of patients' mononuclear cells to stimulate allogeneic T cells. This effect was associated with significant improvement of tetanustoxoid-specific T-cell response. During the IL-2 treatment, the ATRA effect was completely eliminated. To assess the role of IL-2, specimens from 15 patients with metastatic renal cell carcinoma who had been treated with i.v. IL-2 alone were analyzed. In this group also, IL-2 significantly reduced the number and function of dendritic cells as well as T-cell function. These data indicate that ATRA at effective concentrations eliminated ImC, improved myeloid/lymphoid dendritic cell ratio, dendritic cell function, and antigen- specific T-cell response. ATHA treatment did not result in significant toxicity and it could be tested in therapeutic combination with cancer vaccines.