Department of Surgery, University of Virginia, P.O. Box 801329, Charlottesville, VA, 22908, USA.
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
Cancer Immunol Immunother. 2021 Aug;70(8):2151-2164. doi: 10.1007/s00262-020-02844-w. Epub 2021 Jan 16.
The strength and durability of systemic anti-tumor immune responses induced by cancer vaccines depends on adjuvants to support an immunogenic vaccine site microenvironment (VSME). Adjuvants include water-in-oil emulsions with incomplete Freund's adjuvant (IFA) and combinations of toll-like receptor (TLR) agonists, including a preparation containing TLR4 and TLR9 agonists with QS-21 (AS15). IFA-containing vaccines can promote immune cell accumulation at the VSME, whereas effects of AS15 are largely unexplored. Therefore, we assessed innate and adaptive immune cell accumulation and gene expression at the VSME after vaccination with AS15 and compared to effects with IFA. We hypothesized that AS15 would promote less accumulation of innate and adaptive immune cells at the VSME than IFA vaccines. In two clinical trials, patients with resected high-risk melanoma received either a multipeptide vaccine with IFA or a recombinant MAGE-A3 protein vaccine with AS15. Vaccine site biopsies were obtained after one or multiple vaccines. T cells accumulated early after vaccines with AS15, but this was not durable or of the same magnitude as vaccination in IFA. Vaccines with AS15 increased durable expression of DC- and T cell-related genes, as well as PD-L1 and IDO1, suggesting complex activation and regulation of innate and adaptive immune function with AS15. These changes were generally greater with vaccines containing IFA, but IFA induced reduction in myeloid suppressor cells markers. Evidence of tertiary lymphoid structure (TLS) formation was observed with both adjuvants. Our findings highlight adjuvant-dependent changes in immune features at the VSME that may impact systemic immune responses.
癌症疫苗诱导的全身性抗肿瘤免疫反应的强度和持久性取决于佐剂，以支持免疫原性疫苗部位微环境（VSME）。佐剂包括不完全弗氏佐剂（IFA）的水包油乳剂和 Toll 样受体（TLR）激动剂的组合，包括含有 TLR4 和 TLR9 激动剂与 QS-21（AS15）的制剂。IFA 疫苗可促进免疫细胞在 VSME 处的积累，而 AS15 的作用在很大程度上尚未得到探索。因此，我们评估了接种 AS15 后 VSME 处固有和适应性免疫细胞的积累和基因表达，并与 IFA 的作用进行了比较。我们假设 AS15 会比 IFA 疫苗在 VSME 处促进较少的固有和适应性免疫细胞积累。在两项临床试验中，接受过手术的高风险黑色素瘤患者接受了 IFA 多肽疫苗或 AS15 重组 MAGE-A3 蛋白疫苗。接种疫苗后，在一个或多个疫苗后获得了疫苗部位活检。接种 AS15 后，T 细胞会早期积累，但这种积累并不持久，也不如 IFA 疫苗那样持久。AS15 疫苗增加了 DC 和 T 细胞相关基因以及 PD-L1 和 IDO1 的持久表达，这表明 AS15 对固有和适应性免疫功能具有复杂的激活和调节作用。这些变化在含有 IFA 的疫苗中通常更大，但 IFA 诱导了髓系抑制细胞标志物的减少。用两种佐剂都观察到了三级淋巴结构（TLS）的形成证据。我们的发现强调了 VSME 处免疫特征的佐剂依赖性变化，这可能会影响全身免疫反应。
