Cancer Immunology, Immunotherapy and Tolerance Program, Georgia Cancer Center, Augusta University, 1410 Laney Walker Blvd., CN-4121, Augusta, GA, 30912, USA.
Department of Otolaryngology, Head and Neck Surgery, Asahikawa Medical University, Asahikawa, Japan.
Cancer Immunol Immunother. 2018 Jul;67(7):1091-1103. doi: 10.1007/s00262-018-2164-6. Epub 2018 Apr 25.
Cytotoxic T lymphocytes (CTLs) are effective components of the immune system capable of destroying tumor cells. Generation of CTLs using peptide vaccines is a practical approach to treat cancer. We have previously described a peptide vaccination strategy that generates vast numbers of endogenous tumor-reactive CTLs after two sequential immunizations (prime-boost) using poly-ICLC adjuvant, which stimulates endosomal toll-like receptor 3 (TLR3) and cytoplasmic melanoma differentiation antigen 5 (MDA5). Dendritic cells (DCs) play an important role not only in antigen presentation but are critical in generating costimulatory cytokines that promote CTL expansion. Poly-ICLC was shown to be more effective than poly-IC in generating type-I interferon (IFN-I) in various DC subsets, through its enhanced ability to escape the endosomal compartment and stimulate MDA5. In our system, IFN-I did not directly function as a T cell costimulatory cytokine, but enhanced CTL expansion through the induction of IL15. With palmitoylated peptide vaccines, CD8α+ DCs were essential for peptide crosspresentation. For vaccine boosts, non-professional antigen-presenting cells were able to present minimal epitope peptides, but DCs were still required for CTL expansions through the production of IFN-I mediated by poly-ICLC. Overall, these results clarify the roles of DCs, TLR3, MDA5, IFN-I and IL15 in the generation of vast and effective antitumor CTL responses using peptide and poly-IC vaccines.
细胞毒性 T 淋巴细胞（CTLs）是免疫系统的有效组成部分，能够破坏肿瘤细胞。使用肽疫苗生成 CTLs 是治疗癌症的一种实用方法。我们之前描述了一种肽疫苗接种策略，该策略使用聚肌苷酸（poly-ICLC）佐剂进行两次序贯免疫（prime-boost）后，可产生大量内源性肿瘤反应性 CTLs，聚肌苷酸（poly-ICLC）佐剂可刺激内体 Toll 样受体 3（TLR3）和细胞质黑色素瘤分化抗原 5（MDA5）。树突状细胞（DCs）不仅在抗原呈递中发挥重要作用，而且在生成促进 CTL 扩增的共刺激细胞因子方面也至关重要。聚肌苷酸（poly-ICLC）通过增强逃避内体区室并刺激 MDA5 的能力，比聚肌苷酸（poly-IC）在各种 DC 亚群中更有效地生成 I 型干扰素（IFN-I）。在我们的系统中，IFN-I 并未直接作为 T 细胞共刺激细胞因子发挥作用，而是通过诱导 IL15 增强 CTL 扩增。对于棕榈酰化肽疫苗，CD8α+ DCs 对于肽交叉呈递至关重要。对于疫苗加强，非专业抗原呈递细胞能够呈递最小表位肽，但 DCs 仍然需要通过 poly-ICLC 介导的 IFN-I 产生来进行 CTL 扩增。总体而言，这些结果阐明了 DCs、TLR3、MDA5、IFN-I 和 IL15 在使用肽和聚肌苷酸疫苗生成大量有效抗肿瘤 CTL 反应中的作用。
