i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal; ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.
i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal.
Acta Biomater. 2017 Nov;63:96-109. doi: 10.1016/j.actbio.2017.09.016. Epub 2017 Sep 14.
Anticancer immune responses depend on efficient presentation of tumor antigens and co-stimulatory signals provided by antigen-presenting cells (APCs). However, it is described that immature dendritic cells (DCs) and macrophages at the tumor site may have an immunosuppressive profile, which limits the activity of effector T cells and supports tumor progression. Therapeutic targeting of these innate immune cells, either aiming at their elimination or re-polarization towards an immunostimulatory profile, has been pointed as an attractive approach to control tumor progression. In the present work, we assessed the potential of Chitosan (Ch)/Poly(γ-glutamic acid) (γ-PGA) nanoparticles (NPs) to modulate macrophages and DCs inflammatory profile and to impair their ability to promote cancer cell invasion. Interestingly, Ch/γ-PGA NPs, prepared by co-acervation method, induced an immunostimulatory DCs phenotype, enhancing the expression of the co-stimulatory molecules CD86, CD40 and HLA-DR, and the secretion of the pro-inflammatory cytokines TNF-α, IL-12p40 and IL-6. Furthermore, Ch/γ-PGA NPs re-educated IL-10-stimulated macrophages towards a pro-inflammatory profile, decreasing the expression of CD163 and promoting the secretion of IL-12p40 and TNF-α. These alterations in the immune cells phenotype promoted CD4 and CD8 T cell activation/proliferation and partially inhibited APCs' ability to induce colorectal cancer cell invasion. Overall, our findings open new perspectives on the use of Ch/γ-PGA NPs as an immunomodulatory therapy for antigen-presenting cells reprogramming, providing a new tool for anticancer therapies.
The immune system is responsible to detect and destroy abnormal cells preventing the development of cancer. However, the immunosuppressive tumor microenvironment can compromise the immune response favoring tumor progression. Thus, immune system modulation towards an immunostimulatory profile can improve anticancer therapies. This research focus on the development of chitosan/poly(γ-glutamic acid) nanoparticles (NPs) to modulate human antigen-presenting cells (APCs) phenotype and to counteract their pro-invasive capacity. Interestingly, Ch/γ-PGA NPs had a prominent effect in inducing macrophages and dendritic cells immunostimulatory phenotype, thus favoring T cell proliferation and inhibiting colorectal cancer cell invasion. We propose that their combination with other immunomodulatory drugs or conventional anticancer therapies can improve patients' outcome.
抗癌免疫反应取决于肿瘤抗原的有效呈递和抗原呈递细胞 (APC) 提供的共刺激信号。然而，据描述，肿瘤部位的未成熟树突状细胞 (DC) 和巨噬细胞可能具有免疫抑制特征，这限制了效应 T 细胞的活性并支持肿瘤进展。针对这些先天免疫细胞的治疗靶向，无论是旨在消除它们还是使其向免疫刺激特征重新极化，都被认为是控制肿瘤进展的一种有吸引力的方法。在本工作中，我们评估了壳聚糖 (Ch)/聚 (γ-谷氨酸) (γ-PGA) 纳米颗粒 (NPs) 调节巨噬细胞和 DC 炎症表型并损害其促进癌细胞侵袭能力的潜力。有趣的是，通过共凝聚法制备的 Ch/γ-PGA NPs 诱导免疫刺激型 DC 表型，增强共刺激分子 CD86、CD40 和 HLA-DR 的表达，并分泌促炎细胞因子 TNF-α、IL-12p40 和 IL-6。此外，Ch/γ-PGA NPs 将 IL-10 刺激的巨噬细胞重新编程为促炎表型，降低 CD163 的表达并促进 IL-12p40 和 TNF-α 的分泌。这些免疫细胞表型的改变促进了 CD4 和 CD8 T 细胞的激活/增殖，并部分抑制了 APC 诱导结直肠癌细胞侵袭的能力。总的来说，我们的研究结果为 Ch/γ-PGA NPs 作为抗原呈递细胞重编程的免疫调节治疗开辟了新的前景，为癌症治疗提供了新的工具。
免疫系统负责检测和破坏异常细胞，防止癌症的发展。然而，免疫抑制性肿瘤微环境会损害免疫反应，有利于肿瘤的进展。因此，向免疫刺激表型的免疫系统调节可以改善抗癌疗法。本研究专注于开发壳聚糖/聚 (γ-谷氨酸) 纳米颗粒 (NPs) 来调节人抗原呈递细胞 (APC) 的表型，并对抗其促侵袭能力。有趣的是，Ch/γ-PGA NPs 对诱导巨噬细胞和树突状细胞免疫刺激表型具有显著作用，从而促进 T 细胞增殖并抑制结直肠癌细胞侵袭。我们提出，将它们与其他免疫调节药物或常规抗癌疗法结合使用可以改善患者的预后。
