A Tumor-Peptide-Based Nanoparticle Vaccine Elicits Efficient Tumor Growth Control in Antitumor Immunotherapy
A Tumor-Peptide-Based Nanoparticle Vaccine Elicits Efficient Tumor Growth Control in Antitumor Immunotherapy
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DOI：
10.1158/1535-7163.mct-18-0764
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发表时间：
2019-06-01
影响因子：
5.7
通讯作者：
Knuschke, Torben
中科院分区：
文献类型：
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作者：
Hesse, Carolin;Kollenda, Sebastian;Knuschke, Torben
免疫系统对免疫活性寡核苷酸（如Toll样受体配体CpG）的识别导致抗体和T细胞应答增加。全身应用通常导致免疫系统的不需要的全身性非抗原特异性激活。纳米颗粒是小分子和大分子的理想载体。最近，我们已经证明，磷酸钙（CaP）与CpG功能化纳米粒子，和病毒抗原能够诱导特异性T细胞免疫，保护小鼠免受病毒感染，并有效地重新激活慢性逆转录病毒感染期间耗尽的CD 8（+）T细胞区室。因此，CaP纳米颗粒是用于治疗应用的有前景的疫苗载体。在这项研究中，我们研究了这些纳米颗粒在小鼠异种移植结直肠癌模型中的治疗潜力。用CpG和肿瘤模型抗原功能化的CaP纳米颗粒的治疗性疫苗接种以I型干扰素依赖性方式增加了肿瘤中细胞毒性CD 8（+）T细胞的频率，这与可溶性CpG和抗原的全身施用相比，伴随着显著抑制的肿瘤生长。CaP纳米颗粒和针对PD-L1的免疫检查点阻断剂的联合治疗进一步增强了细胞毒性CD 8（+）T细胞应答并根除了肿瘤。引人注目的是，用CpG官能化的CaP纳米颗粒和原代肿瘤细胞裂解物接种也足以控制肿瘤生长。总之，我们的研究结果代表了使用CaP纳米颗粒作为有效的癌症疫苗载体的转化方法。
Recognition of immunoactive oligonucleotides by the immune system, such as Toll-like receptor ligand CpG, leads to increased antibody and T-cell responses. Systemic application often results in unwanted generalized nonantigen-specific activation of the immune system. nanoparticles are ideal carriers for small and large molecules. Recently, we have demonstrated that calcium phosphate (CaP) nanoparticles functionalized with CpG, and viral antigens are able to induce specific T-cell immunity that protects mice against viral infection and efficiently reactivates the exhausted CD8(+) T-cell compartment during chronic retroviral infection. Therefore, CaP nanoparticles are promising vaccine vehicles for therapeutic applications. In this study, we investigated the therapeutic potential use of these nanoparticles in a murine xenograft colorectal cancer model. Therapeutic vaccination with CaP nanoparticles functionalized with CpG and tumor model antigens increased the frequencies of cytotoxic CD8(+) T cells in the tumor in a type I interferon-dependent manner, This was accompanied with significantly repressed tumor growth in contrast to the systemic administration of soluble CpG and antigens. Combination therapy of CaP nanoparticles and immune checkpoint blocker against PD-L1 further enhanced the cytotoxic CD8(+) T-cell response and eradicated the tumors. Strikingly, vaccination with CaP nanoparticles functionalized with CpG and a primary tumor cell lysate was also sufficient to control the tumor growth. In conclusion, our results represent a translational approach for the use of CaP nanoparticles as a potent cancer vaccine vehicle.