Collignon Aurélie, Silvy Françoise, Robert Stéphane, Trad Malika, Germain Sébastien, Nigri Jérémy, André Frédéric, Rigot Véronique, Tomasini Richard, Bonnotte Bernard, Lombardo Dominique, Mas Eric, Beraud Evelyne
Aix Marseille Univ, INSERM, CRO2, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Marseille, France.
Aix Marseille Univ, INSERM, INRA, C2VN, Marseille, France.
Oncoimmunology. 2018 Sep 25;7(12):e1504727. doi: 10.1080/2162402X.2018.1504727. eCollection 2018.
Pancreatic adenocarcinoma (PAC) has a poor prognosis. One treatment approach, investigated here, is to reinforce antitumor immunity. Dendritic cells (DCs) are essential for the development and regulation of adaptive host immune responses against tumors. A major role for DCs may be as innate tumoricidal effector cells. We explored the efficacy of vaccination with immature (i)DCs, after selecting optimal conditions for generating immunostimulatory iDCs. We used two models, C57BL/6Jrj mice with ectopic tumors induced by the PAC cell line, Panc02, and genetically engineered (KIC) mice developing PAC. Therapeutic iDC-vaccination resulted in a significant reduction in tumor growth in C57BL/6Jrj mice and prolonged survival in KIC mice. Prophylactic iDC-vaccination prevented subcutaneous tumor development. These protective effects were long-lasting in Panc02-induced tumor development, but not in melanoma. iDC-vaccination impacted the immune status of the hosts by greatly increasing the percentage of CD8 T-cells, and natural killer (NK)1.1 cells, that express granzyme B associated with Lamp-1 and IFN-γ. Efficacy of iDC-vaccination was CD8 T-cell-dependent but NK1.1 cell-independent. We demonstrated the ability of DCs to produce peroxynitrites and to kill tumor cells; this killing activity involved peroxynitrites. Altogether, these findings make killer DCs the pivotal actors in the beneficial clinical outcome that accompanies antitumor immune responses. We asked whether efficacy can be improved by combining DC-vaccination with the FOLFIRINOX regimen. Combined treatment significantly increased the lifespan of KIC mice with PAC. Prolonged treatment with FOLFIRINOX clearly augmented this beneficial effect. Combining iDC-vaccination with FOLFIRINOX may therefore represent a promising therapeutic option for patients with PAC.
胰腺腺癌（PAC）预后较差。本文所研究的一种治疗方法是增强抗肿瘤免疫力。树突状细胞（DCs）对于适应性宿主抗肿瘤免疫反应的发展和调节至关重要。DCs的一个主要作用可能是作为先天性肿瘤杀伤效应细胞。在选择了产生免疫刺激未成熟DCs的最佳条件后，我们探索了用未成熟DCs进行疫苗接种的效果。我们使用了两种模型，一种是用PAC细胞系Panc02诱导产生异位肿瘤的C57BL/6Jrj小鼠，另一种是发生PAC的基因工程（KIC）小鼠。治疗性未成熟DCs疫苗接种导致C57BL/6Jrj小鼠的肿瘤生长显著减少，并延长了KIC小鼠的生存期。预防性未成熟DCs疫苗接种可预防皮下肿瘤的发生。这些保护作用在Panc02诱导的肿瘤发展中是持久的，但在黑色素瘤中并非如此。未成熟DCs疫苗接种通过大幅增加表达与Lamp-1和IFN-γ相关的颗粒酶B的CD8 T细胞和自然杀伤（NK）1.1细胞的百分比，影响宿主的免疫状态。未成熟DCs疫苗接种的疗效依赖于CD8 T细胞，但不依赖于NK1.1细胞。我们证明了DCs产生过氧亚硝酸盐并杀死肿瘤细胞的能力；这种杀伤活性涉及过氧亚硝酸盐。总之，这些发现使杀伤性DCs成为抗肿瘤免疫反应所伴随的有益临床结果中的关键因素。我们询问将DCs疫苗接种与FOLFIRINOX方案联合使用是否可以提高疗效。联合治疗显著延长了患有PAC的KIC小鼠的寿命。FOLFIRINOX的长期治疗明显增强了这种有益效果。因此，将未成熟DCs疫苗接种与FOLFIRINOX联合使用可能是PAC患者一种有前景的治疗选择。
