Dexamethasone turns tumor antigen-presenting cells into tolerogenic dendritic cells with T cell inhibitory functions
Dexamethasone turns tumor antigen-presenting cells into tolerogenic dendritic cells with T cell inhibitory functions
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DOI：
10.1016/j.imbio.2019.05.011
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发表时间：
2019-09-01
期刊：
影响因子：
2.8
通讯作者：
Lopez, Mercedes N.
中科院分区：
文献类型：
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作者：
Falcon-Beas, Cristian;Tittarelli, Andres;Lopez, Mercedes N.
背景：树突状细胞（DC）通常具有免疫原性，但它们也能够在抗炎条件下诱导耐受。基于负载同种异基因黑色素瘤细胞裂解物的自体DC（TRIMEL/DC）的免疫疗法可诱导免疫反应并提高黑色素瘤患者的生存率。糖皮质激素可以抑制DC的成熟和功能，导致DC介导的T细胞反应抑制。方法：检测广泛用于癌症治疗的糖皮质激素地塞米松对TRIMEL/DC表型和免疫原性的影响。地塞米松在具有低成熟表面标志物表达的TRIMEL/DC上诱导半成熟表型，减少促炎细胞因子诱导（IL-1 β和IL-12）和增加调节细胞因子（IL-10和TGF-β）的释放。地塞米松处理的TRIMEL/DC抑制同种异体CD 4（+）T细胞增殖和细胞因子释放（IFN γ、TNF-α和IL-17）。共培养黑色素瘤特异性记忆肿瘤浸润淋巴细胞与地塞米松处理的TRIMEL/DC抑制增殖和效应T细胞的活动，包括细胞因子分泌和抗黑色素瘤cytotoxic.Conclusions：这些研究结果表明，地塞米松抑制黑色素瘤细胞裂解物介导的DC成熟，产生一个强大的耐受性样DC表型，抑制黑色素瘤特异性效应T细胞的活动。这些结果表明，地塞米松诱导的免疫抑制可能会干扰DC为基础的黑色素瘤疫苗的临床疗效，必须考虑到对癌症的细胞治疗的最佳设计。
Background: Dendritic cells (DCs) are usually immunogenic, but they are also capable of inducing tolerance under anti-inflammatory conditions. Immunotherapy based on autologous DCs loaded with an allogeneic melanoma cell lysate (TRIMEL/DCs) induces immunological responses and increases melanoma patient survival. Glucocorticoids can suppress DC maturation and function, leading to a DC-mediated inhibition of T cell responses.Methods: The effect of dexamethasone, a glucocorticoid extensively used in cancer therapies, on TRIMEL/DCs phenotype and immunogenicity was examined.Results: Dexamethasone induced a semi-mature phenotype on TRIMEL/DC with low maturation surface marker expressions, decreased pro-inflammatory cytokine induction (IL-1 beta and IL-12) and increased release of regulatory cytokines (IL-10 and TGF-beta). Dexamethasone-treated TRIMEL/DCs inhibited allogeneic CD4(+) T cell proliferation and cytokine release (IFN gamma, TNF-alpha and IL-17). Co-culturing melanoma-specific memory tumor-infiltrating lymphocytes with dexamethasone-treated TRIMEL/DC inhibited proliferation and effector T cell activities, including cytokine secretion and anti-melanoma cytotoxicity.Conclusions: These findings suggest that dexamethasone repressed melanoma cell lysate-mediated DC maturation, generating a potent tolerogenic-like DC phenotype that inhibited melanoma-specific effector T cell activities. These results suggest that dexamethasone-induced immunosuppression may interfere with the clinical efficacy of DC-based melanoma vaccines, and must be taken into account for optimal design of cellular therapy against cancer.