Department of Microbiology and Immunology, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Translational and Clinical Division, ViGenCell Inc., Seoul, Korea.
Cancer Res Treat. 2020 Jul;52(3):747-763. doi: 10.4143/crt.2019.721. Epub 2020 Feb 14.
Successful tumor eradication primarily depends on generation and maintenance of a large population of tumor-reactive CD8 T cells. Dendritic cells (DCs) are well-known potent antigen-presenting cells and have applied to clinics as potent antitumor therapeutic agents. However, high cost and difficulty in obtaining sufficient amounts for clinical use are the crucial drawbacks of DC-based vaccines. Here, we aimed to develop T cell-based vaccine capable of eliciting potent antitumor therapeutic effects by providing effective costimulatory signals.
Antigenic peptide-loaded T cells transfected with retrovirus encoding costimulatory ligands CD70, CD80, OX40L, or 4-1BBL were assessed for antigen-specific CD8 T-cell responses and evaluated antitumor effects along with immunization of a mixture of synthetic peptides, poly-IC and anti-CD40 antibodies (TriVax).
T cells expressing CD70 (CD70-T) exhibited similar level of stimulatory functionality and therapeutic efficacy as DCs. Moreover, CD70-T prime followed by TriVax booster heterologous vaccination elicited therapeutic antitumor effect against B16 melanoma where mediated by CD8 T cells but not CD4 T cells or natural killer cells. The combination with programmed death-ligand 1 blockade led to potent therapeutic efficacy which exhibited increased tumor-infiltrating CD8 T cells. CD70-T pulsed with multi-antigenic peptide generated multiple antigen-specific polyvalent CD8 T cells that were capable of inhibiting tumor growth effectively. Moreover, CD70-T vaccination resulted in higher expansion and migration of adoptively transferred T cells into tumor sites and elicits enhanced therapeutic effects with peptide-based booster immu-nization.
These results imply that T cells endowed with CD70 enable the design of effective vaccination strategies against solid cancer, which may overcome current limitations of DC-based vaccines.
肿瘤的成功消除主要取决于肿瘤反应性 CD8 T 细胞群体的产生和维持。树突状细胞（DCs）是众所周知的有效的抗原呈递细胞，并已被应用于临床作为有效的抗肿瘤治疗剂。然而，基于 DC 的疫苗的关键缺点是成本高且难以获得足够用于临床使用的数量。在这里，我们旨在开发能够通过提供有效的共刺激信号来引发有效抗肿瘤治疗效果的 T 细胞疫苗。
用逆转录病毒转染负载抗原肽的 T 细胞，该逆转录病毒编码共刺激配体 CD70、CD80、OX40L 或 4-1BBL，评估其对抗原特异性 CD8 T 细胞反应的影响，并评估与混合合成肽、聚肌苷酸和抗 CD40 抗体（TriVax）免疫接种相关的抗肿瘤作用。
表达 CD70 的 T 细胞（CD70-T）表现出与 DC 相似的刺激功能和治疗功效。此外，CD70-T 初免后用 TriVax 加强异源疫苗接种可引发针对 B16 黑色素瘤的治疗性抗肿瘤作用，该作用是由 CD8 T 细胞介导的，而不是由 CD4 T 细胞或自然杀伤细胞介导的。与程序性死亡配体 1 阻断的联合作用导致了强大的治疗效果，表现为肿瘤浸润性 CD8 T 细胞增加。用多抗原肽脉冲的 CD70-T 产生了能够有效抑制肿瘤生长的多种抗原特异性多价 CD8 T 细胞。此外，CD70-T 疫苗接种导致更多的过继转移 T 细胞进入肿瘤部位，并通过基于肽的加强免疫接种产生增强的治疗效果。
这些结果表明，赋予 CD70 的 T 细胞能够设计针对实体癌的有效疫苗接种策略，这可能克服基于 DC 的疫苗的当前局限性。
