TLR9 plus STING Agonist Adjuvant Combination Induces Potent Neopeptide T Cell Immunity and Improves Immune Checkpoint Blockade Efficacy in a Tumor Model
Melisa D. Castro Eiro, Kou Hioki, Ling Li, Merel E. P. Wilmsen, Caoimhe H. Kiernan, Inge Brouwers-Haspels, Marjan van Meurs, Manzhi Zhao, Harm de Wit, Dwin G. B. Grashof, Harmen J. G. van de Werken, Yvonne M. Mueller, Christopher Schliehe, Burcu Temizoz, Kouji Kobiyama, Ken J. Ishii, Peter D. Katsikis
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Abstract Immune checkpoint blockade (ICB) immunotherapies have emerged as promising strategies for the treatment of cancer; however, there remains a need to improve their efficacy. Determinants of ICB efficacy are the frequency of tumor mutations, the associated neoantigens, and the T cell response against them. Therefore, it is expected that neoantigen vaccinations that boost the antitumor T cell response would improve ICB therapy efficacy. The aim of this study was to develop a highly immunogenic vaccine using pattern recognition receptor agonists in combination with synthetic long peptides to induce potent neoantigen-specific T cell responses. We determined that the combination of the TLR9 agonist K-type CpG oligodeoxynucleotides (K3 CpG) with the STING agonist c-di-AMP (K3/c-di-AMP combination) significantly increased dendritic cell activation. We found that immunizing mice with 20-mer of either an OVA peptide, low-affinity OVA peptides, or neopeptides identified from mouse melanoma or lung mesothelioma, together with K3/c-di-AMP, induced potent Ag-specific T cell responses. The combined K3/c-di-AMP adjuvant formulation induced 10 times higher T cell responses against neopeptides than the TLR3 agonist polyinosinic:polycytidylic acid, a derivative of which is the leading adjuvant in clinical trials of neoantigen peptide vaccines. Moreover, we demonstrated that our K3/c-di-AMP vaccine formulation with 20-mer OVA peptide was capable of controlling tumor growth and improving survival in B16-F10-OVA tumor-bearing C57BL/6 mice and synergized with anti-PD-1 treatment. Together, our findings demonstrate that the K3/c-di-AMP vaccine formulation induces potent T cell immunity against synthetic long peptides and is a promising candidate to improve neoantigen vaccine platform.
TLR9 加 STING 激动剂辅助剂组合可诱导肿瘤模型中的强效新肽 T 细胞免疫并提高免疫检查点阻断剂的疗效
摘要 免疫检查点阻断（ICB）免疫疗法已成为治疗癌症的有前途的策略，但仍需提高其疗效。决定 ICB 疗效的因素包括肿瘤突变的频率、相关的新抗原以及针对它们的 T 细胞反应。因此，新抗原疫苗可增强抗肿瘤 T 细胞的反应，从而提高 ICB 的疗效。本研究旨在开发一种高免疫原性疫苗，利用模式识别受体激动剂与合成长肽相结合，诱导有效的新抗原特异性 T 细胞反应。我们发现，TLR9 激动剂 K 型 CpG 寡脱氧核苷酸（K3 CpG）与 STING 激动剂 c-di-AMP 组合（K3/c-di-AMP 组合）能显著提高树突状细胞的活化。我们发现，用 20-mer 的 OVA 肽、低亲和力 OVA 肽或从小鼠黑色素瘤或肺间皮瘤中鉴定出的新肽与 K3/c-di-AMP 一起免疫小鼠，可诱导强效的 Ag 特异性 T 细胞反应。K3/c-di-AMP复合佐剂配方诱导的针对新肽的T细胞应答比TLR3激动剂聚肌苷酸：聚胞苷酸高10倍，后者的衍生物是新抗原肽疫苗临床试验中的主要佐剂。此外，我们还证明了含有 20-mer OVA 肽的 K3/c-di-AMP 疫苗制剂能够控制肿瘤生长，提高 B16-F10-OVA 肿瘤 C57BL/6 小鼠的存活率，并与抗 PD-1 治疗协同作用。总之，我们的研究结果表明，K3/c-di-AMP 疫苗制剂能诱导针对合成长肽的强效 T 细胞免疫，是一种有希望改进新抗原疫苗平台的候选药物。
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