Sethi Shiv K, Bradley Claire E, Bialkowski Lukas, Pang Yuk Ying, Thompson Cynthia D, Schiller John T, Çuburu Nicolas
National Cancer Institute, NIH, Bethesda, MD, USA.
Beckman Coulter, Bethesda, USA.
NPJ Vaccines. 2025 Apr 25;10(1):84. doi: 10.1038/s41541-025-01131-y.
Intratumoral (IT) immunotherapy can stimulate the tumor microenvironment and enhance anti-tumor immunity. We investigated IT delivery of three licensed viral vaccines-Shingrix (VZV shingles), Gardasil-9 (HPV), and Spikevax (SARS-CoV-2)-in prevaccinated mice using the murine tumor model TC-1, which expresses HPV16 oncogenes E6 and E7. Shingrix IT injection often induced tumor regression and resistance to secondary challenge. Injecting a VZV glycoprotein E (gE)-derived MHC-II-restricted peptide with polyI:C also led to durable remission, highlighting the role of gE-specific CD4 T cells. While Gardasil-9 IT injection alone was ineffective, combining a HPV L1-derived MHC-I-restricted peptide with polyI:C or Shingrix enhanced tumor regression. Both approaches elicited CD8 T cells against the E7 tumor viral oncoprotein. Tumor microenvironment analysis revealed remodeling of the myeloid compartment, significant induction of IFN-γ, TNF-α, and CXCL9 and broad gene expression reprograming. In a dual-flank model, IT injection of Shingrix with an MHC-I-restricted E7 tumor-specific peptide eliminated primary and non-injected tumors. Finally, Spikevax IT injection showed modest tumor growth delay, while improved control was observed with a SARS-CoV-2 spike-derived MHC-I-restricted peptide and polyI:C. These results demonstrate the potential of licensed vaccines as promising platforms for IT immunotherapy, either alone or combined with vaccine- or tumor-derived MHC-I-restricted peptide epitopes.
瘤内（IT）免疫疗法可刺激肿瘤微环境并增强抗肿瘤免疫力。我们使用表达人乳头瘤病毒16型（HPV16）致癌基因E6和E7的小鼠肿瘤模型TC-1，研究了三种已获许可的病毒疫苗——欣安立适（水痘带状疱疹病毒[VZV]带状疱疹疫苗）、九价重组人乳头瘤病毒疫苗（Gardasil-9，HPV疫苗）和mRNA-1273（Spikevax，严重急性呼吸综合征冠状病毒2[SARS-CoV-2]疫苗）在预先接种疫苗的小鼠中的瘤内递送情况。欣安立适瘤内注射常常诱导肿瘤消退并产生对二次攻击的抗性。将一种源自VZV糖蛋白E（gE）的主要组织相容性复合体II类（MHC-II）限制性肽与聚肌胞苷酸（polyI:C）一起注射也导致持久缓解，突出了gE特异性CD4 T细胞的作用。虽然单独的Gardasil-9瘤内注射无效，但将一种源自HPV L1的MHC-I限制性肽与polyI:C或欣安立适联合使用可增强肿瘤消退。两种方法均引发了针对E7肿瘤病毒致癌蛋白的CD8 T细胞。肿瘤微环境分析揭示了髓系区室的重塑、干扰素-γ（IFN-γ）、肿瘤坏死因子-α（TNF-α）和CXC趋化因子9（CXCL9）的显著诱导以及广泛的基因表达重编程。在双侧肿瘤模型中，将欣安立适与一种MHC-I限制性E7肿瘤特异性肽进行瘤内注射消除了原发性肿瘤和未注射的肿瘤。最后，Spikevax瘤内注射显示出适度的肿瘤生长延迟，而使用一种源自SARS-CoV-2刺突蛋白的MHC-I限制性肽和polyI:C则观察到更好的控制效果。这些结果证明了已获许可的疫苗作为IT免疫疗法有前景的平台的潜力，无论是单独使用还是与疫苗或肿瘤衍生的MHC-I限制性肽表位联合使用。
