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<p>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<sup>+</sup> 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<sup>+</sup> 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.</p>

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Repurposing anti-viral subunit and mRNA vaccines T cell immunity for intratumoral immunotherapy against solid tumors

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月25日

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  • Shiv K. Sethi,
  • Claire E. Bradley,
  • Lukas Bialkowski,
  • Yuk Ying Pang,
  • Cynthia D. Thompson,
  • John T. Schiller,
  • Nicolas Çuburu

摘要

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.