Myeloid cells orchestrate systemic immunosuppression, impairing the efficacy of immunotherapy against HPVþ cancers

Gabriele Galliverti, Stephan Wullschleger, Melanie Tichet, Dhaarini Murugan, Nadine Zangger, Wesley Horton, Alan J. Korman, Lisa M. Coussens, Melody A. Swartz, Douglas Hanahan

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Cancers induced by human papillomaviruses (HPV) should be responsive to immunotherapy by virtue of expressing the immunogenic oncoproteins E6/E7. However, advanced forms of cervical cancer, driven by HPV, are poorly responsive to immune response–enhancing treatments involving therapeutic vaccination against these viral neoantigens. Leveraging a transgenic mouse model of HPV-derived cancers, K14HPV16/H2b, we demonstrated that a potent nanoparticle-based E7 vaccine, but not a conventional “liquid” vaccine, induced E7 tumor antigen–specific CD8þ T cells in cervical tumor–bearing mice. Vaccination alone or in combination with anti-PD-1/anti-CTLA4 did not elicit tumor regression nor increase CD8þ T cells in the tumor microenvironment (TME), suggesting the presence of immune-suppressive barriers. Patients with cervical cancer have poor dendritic cell functions, have weak cytotoxic lymphocyte responses, and demonstrate an accumulation of myeloid cells in the periphery. Here, we illustrated that myeloid cells in K14HPV16/H2b mice possess potent immunosuppressive activity toward antigen-presenting cells and CD8þ T cells, dampening antitumor immunity. These immune-inhibitory effects inhibited synergistic effects of combining our oncoprotein vaccine with immune checkpoint–blocking antibodies. Our data highlighted a link between HPV-induced cancers, systemic amplification of myeloid cells, and the detrimental effects of myeloid cells on CD8þ T-cell activation and recruitment into the TME. These results established immunosuppressive myeloid cells in lymphoid organs as an HPVþ cancer–induced means of circumventing tumor immunity that will require targeted abrogation to enable the induction of efficacious antitumor immune responses.

Original languageEnglish (US)
Pages (from-to)131-145
Number of pages15
JournalCancer Immunology Research
Volume8
Issue number1
DOIs
StatePublished - 2020

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

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