IRMB, University of Montpellier, INSERM, Montpellier, France.
CHU Montpellier, Montpellier, France.
Front Immunol. 2019 Nov 28;10:2693. doi: 10.3389/fimmu.2019.02693. eCollection 2019.
Immunotherapy, which is seen as a major tool for cancer treatment, requires, in some cases, the presence of several agents to maximize its effects. Adjuvants can enhance the effect of other agents. However, despite their long-time use, only a few adjuvants are licensed today, and their use in cancer treatment is rare. Azoximer bromide, marketed under the trade name Polyoxidonium® (PO), is a copolymer of N-oxidized 1,4-ethylenepiperazine and (N-carboxyethyl)-1,4-ethylene piperazinium bromide. It has been described as an immune adjuvant and immunomodulator that is clinically used with excellent tolerance. PO is used in the treatment and prophylaxis of diseases connected with damage to the immune system, and there is interest in testing it in antitumor therapy. We show here that PO treatment for 1 week induced positive pathological changes in 6 out of 20 patients with breast cancer, including complete response in a triple-negative patient. This correlated with an increased tumor CD4 T-lymphocyte infiltration. The immune effects of PO are associated with myeloid cell activation, and little is known about the action of PO on lymphocyte lineages, such as natural killer (NK) and T cells. We reveal that PO increases T-cell proliferation without negative effects on any activation marker. PO does not affect dendritic cell (DC) viability and increases the expansion of immature DC (iDC) and mature DC (mDC) at 100 μg/ml, and it stimulates expression of several DC co-stimulatory molecules, inducing the proliferation of allogeneic T cells. In contrast, PO decreases DC viability when added at day 5 post-expansion. PO is not toxic for NK cells at doses up to 100 μM and does not affect their activation, maturation, and cytotoxicity but tends to increase degranulation. This could be beneficial against target cells that show low sensitivity to NK cells, e.g., solid tumor cells. Finally, we have found great variability in PO response between donors. In summary, our results show that PO increases the number of costimulatory molecules on DC that prime T cells, favoring the production of effector T cells. This may support the future clinical development of PO in cancer treatment.
免疫疗法被视为癌症治疗的主要手段之一，在某些情况下需要多种药物联合使用以最大限度地发挥疗效。佐剂可以增强其他药物的效果。然而，尽管它们已经使用了很长时间，但目前只有少数佐剂获得了许可，并且它们在癌症治疗中的应用很少。溴化阿佐西莫（azoximer bromide），商品名为聚氧化烯（PO），是 N-氧化 1,4-亚乙基哌嗪和（N-羧乙基）-1,4-亚乙基哌嗪溴化物的共聚物。它被描述为一种免疫佐剂和免疫调节剂，具有良好的耐受性，在临床上得到了应用。PO 用于治疗和预防与免疫系统损伤相关的疾病，并且人们对其在抗肿瘤治疗中的应用很感兴趣。我们在这里展示，PO 治疗 1 周后，20 名乳腺癌患者中有 6 名出现了阳性病理变化，包括三阴性患者的完全缓解。这与肿瘤 CD4 T 淋巴细胞浸润增加相关。PO 的免疫作用与髓样细胞激活有关，而对 PO 对淋巴细胞谱系（如自然杀伤（NK）和 T 细胞）的作用知之甚少。我们发现，PO 增加了 T 细胞的增殖，而对任何激活标志物没有负面影响。PO 不影响树突状细胞（DC）的活力，并且在 100μg/ml 时增加不成熟 DC（iDC）和成熟 DC（mDC）的扩增，并刺激几种 DC 共刺激分子的表达，诱导同种异体 T 细胞的增殖。相比之下，当在扩增后第 5 天添加时，PO 会降低 DC 的活力。PO 在高达 100μM 的剂量下对 NK 细胞无毒，并且不会影响其激活、成熟和细胞毒性，但倾向于增加脱颗粒。这可能对 NK 细胞敏感性低的靶细胞有益，例如实体瘤细胞。最后，我们发现 PO 对供体之间的反应有很大的差异。总之，我们的结果表明，PO 增加了刺激 T 细胞的 DC 上的共刺激分子数量，有利于效应 T 细胞的产生。这可能支持 PO 在癌症治疗中的未来临床发展。
