Cornwall Scott M J, Wikstrom Matthew, Musk Arthur W, Alvarez John, Nowak Anna K, Nelson Delia J
School of Biomedical Sciences, Immunology and Cancer Group, Curtin University, Perth, Western Australia (WA), Australia; CHIRI Biosciences Research Precinct, Curtin University, Perth, WA, Australia.
Lions Eye institute, University of WA , Nedlands, WA, Australia.
Oncoimmunology. 2015 Aug 31;5(2):e1082028. doi: 10.1080/2162402X.2015.1082028. eCollection 2016 Feb.
Mesothelioma is an almost invariably fatal tumor with chemotherapy extending survival by a few months. One immunotherapeutic strategy is to target dendritic cells (DCs), key antigen-presenting cells involved in antigen presentation, to induce antigen-specific T cell responses. However, DC-targeting will only be effective if DCs are fit-for-purpose, and the functional status of DCs in mesothelioma patients was not clear. We found that mesothelioma patients have significantly decreased numbers of circulating myeloid (m)DC1 cells, mDC2 cells and plasmacytoid (p)DCs relative to healthy age and gender-matched controls. Blood monocytes from patients could not differentiate into immature monocyte-derived DCs (MoDCs), indicated by a significantly reduced ability to process antigen and reduced expression of costimulatory (CD40, CD80 and CD86) and MHC (HLA-DR) molecules, relative to controls. Activation of mesothelioma-derived MoDCs with LPS+/-IFNγ generated partially mature MoDCs, evident by limited upregulation of the maturation marker, CD83, and the costimulatory markers. Attempts to rescue mesothelioma-derived DC function using CD40Ligand(L) also failed, indicated by maintenance of antigen-processing capacity and limited upregulation of CD40, CD83, CD86 and HLA-DR. These data suggest that mesothelioma patients have significant numerical and functional DC defects and that their reduced capacity to process antigen and reduced expression of costimulatory molecules could induce anergized/tolerized T cells. Nonetheless, survival analyses revealed that individuals with mesothelioma and higher than median levels of mDC1s and/or whose MoDCs matured in response to LPS, IFNγ or CD40L lived longer, implying their selection for DC-targeting therapy could be promising especially if combined with another treatment modality.
间皮瘤是一种几乎总是致命的肿瘤，化疗可将生存期延长几个月。一种免疫治疗策略是靶向树突状细胞（DCs），其是参与抗原呈递的关键抗原呈递细胞，以诱导抗原特异性T细胞反应。然而，只有当DCs符合要求时，靶向DC才会有效，而间皮瘤患者中DC的功能状态尚不清楚。我们发现，与年龄和性别匹配的健康对照相比，间皮瘤患者循环中的髓样（m）DC1细胞、mDC2细胞和浆细胞样（p）DCs数量显著减少。与对照相比，患者的血液单核细胞不能分化为未成熟的单核细胞衍生DCs（MoDCs），这表现为处理抗原的能力显著降低以及共刺激分子（CD40、CD80和CD86）和MHC（HLA-DR）分子的表达减少。用LPS+/-IFNγ激活间皮瘤来源的MoDCs产生了部分成熟的MoDCs，这可通过成熟标志物CD83和共刺激标志物的有限上调得以证明。使用CD40配体（L）挽救间皮瘤来源的DC功能的尝试也失败了，这表现为抗原处理能力维持不变以及CD40、CD83、CD86和HLA-DR的上调有限。这些数据表明，间皮瘤患者存在显著的数量和功能DC缺陷，其处理抗原的能力降低以及共刺激分子的表达减少可能会诱导T细胞无反应/耐受。尽管如此，生存分析显示，间皮瘤患者中mDC1水平高于中位数和/或其MoDCs对LPS、IFNγ或CD40L有反应而成熟的个体生存期更长，这意味着选择他们进行靶向DC治疗可能很有前景，特别是如果与另一种治疗方式联合使用。
