Pinzon-Charry Alberto, Maxwell Tammy, Prato Sandro, Furnival Colin, Schmidt Chris, López José Alejandro
Dendritic Cell and Cancer Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland 4006, Australia.
Neoplasia. 2005 Dec;7(12):1123-32. doi: 10.1593/neo.05448.
Dendritic cells (DC) have been implicated in the defective function of the immune system during cancer progression. We have demonstrated that patients with cancer have fewer myeloid (CD11c+) and plasmacytoid (CD123(hi)) DC and a concurrent accumulation of CD11c(-)CD123- immature cells expressing HLA-DR (DR(+)IC). Notably, DR(+)IC from cancer patients have a reduced capacity to stimulate allogeneic T-cells. DR(+)IC are also present in healthy donors, albeit in smaller numbers. In this study, we assessed whether DR(+)IC could have an impact on the immune response by comparing their function with DC counterparts. For this purpose, DR(+)IC and DC were purified and tested in the presentation of antigens through major histocompatibility complex (MHC) II and MHC-I molecules. DR(+)IC were less efficient than DC at presenting antigens to T-cells. DR(+)IC induced a limited activation of T-cells, eliciting poor T-helper (Th) 1 and preferentially inducing Th2-biased responses. Importantly, despite DR(+)IC's poor responsiveness to inflammatory factors, in samples from healthy volunteers and breast cancer patients, CD40 ligation induced phenotypic maturation and interleukin 12 secretion, in turn generating more efficient T-cell responses. These data underscore the importance of inefficient antigen presentation as a mechanism for tumor evasion and suggest an approach to improve the efficacy of DC-based immunotherapy for cancer.
树突状细胞（DC）与癌症进展过程中免疫系统的功能缺陷有关。我们已经证明，癌症患者的髓样（CD11c+）和浆细胞样（CD123(hi)）DC数量较少，同时表达HLA-DR（DR(+)IC）的CD11c(-)CD123-未成熟细胞会积累。值得注意的是，癌症患者的DR(+)IC刺激同种异体T细胞的能力降低。健康供体中也存在DR(+)IC，不过数量较少。在本研究中，我们通过比较DR(+)IC与DC的功能，评估了DR(+)IC是否会对免疫反应产生影响。为此，我们纯化了DR(+)IC和DC，并通过主要组织相容性复合体（MHC）II和MHC-I分子检测它们在抗原呈递中的作用。在将抗原呈递给T细胞方面，DR(+)IC的效率低于DC。DR(+)IC诱导的T细胞激活有限，引发的辅助性T细胞（Th）1反应较差，且优先诱导偏向Th2的反应。重要的是，尽管DR(+)IC对炎症因子的反应性较差，但在健康志愿者和乳腺癌患者的样本中，CD40连接可诱导其表型成熟并分泌白细胞介素12，进而产生更有效的T细胞反应。这些数据强调了低效抗原呈递作为肿瘤逃逸机制的重要性，并提出了一种提高基于DC的癌症免疫治疗疗效的方法。
