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Cancer Immunology Research

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Research Article

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

Gabriele Galliverti, Stephan Wullschleger, Mélanie Tichet, Dhaarini Murugan, Nadine Zangger, Wesley Horton, Alan J Korman, Lisa M. Coussens, Melody A. Swartz and Douglas Hanahan
Gabriele Galliverti
Swiss Institute for Experimental Cancer Research (ISREC), Swiss Federal Institute of Lausanne (EPFL)
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Stephan Wullschleger
Swiss Institute for Experimental Cancer Research (ISREC), Swiss Federal Institute of Lausanne (EPFL)
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Mélanie Tichet
Swiss Institute for Experimental Cancer Research, Swiss Federal Institute of Lausanne
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Dhaarini Murugan
Department of Cell, Developmental & Cancer Biology, Knight Cancer Institute, Oregon Health & Science University
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Nadine Zangger
Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics
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Wesley Horton
Computational Biology Program, Knight Cancer Institute, Oregon Health & Science University
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Alan J Korman
Immunology, Vir Biotechnology, Inc
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  • ORCID record for Alan J Korman
Lisa M. Coussens
Cell, Developmental & Cancer Biology, Oregon Health & Science University
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Melody A. Swartz
Institute for Molecular Engineering, University of Chicago
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Douglas Hanahan
Swiss Institute for Experimental Cancer Research (ISREC), Swiss Federal Institute of Technology Lausanne (EPFL)
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  • For correspondence: douglas.hanahan@epfl.ch
DOI: 10.1158/2326-6066.CIR-19-0315
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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 neo-antigens. 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 CD8+ 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 CD8+ T cells in the tumor microenvironment (TME), suggesting the presence of immune suppressive barriers. Cervical cancer patients have poor dendritic cell functions, 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 towards antigen presenting cells and CD8+ T cells, dampeing 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 CD8+ T cell activation and recruitment into the TME. These results established immunosuppressive myeloid cells in lymphoid organs as an HPV+ cancer-induced means of circumventing tumor immunity that will require targeted abrogation to enable the induction of efficacious anti-tumor immune responses.

  • Received May 1, 2019.
  • Revision received September 6, 2019.
  • Accepted November 14, 2019.
  • Copyright ©2019, American Association for Cancer Research.
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Published OnlineFirst November 26, 2019
doi: 10.1158/2326-6066.CIR-19-0315

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Myeloid cells orchestrate systemic immunosuppression, impairing the efficacy of immunotherapy against HPV+ cancers
Gabriele Galliverti, Stephan Wullschleger, Mélanie Tichet, Dhaarini Murugan, Nadine Zangger, Wesley Horton, Alan J Korman, Lisa M. Coussens, Melody A. Swartz and Douglas Hanahan
Cancer Immunol Res November 26 2019 DOI: 10.1158/2326-6066.CIR-19-0315

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Myeloid cells orchestrate systemic immunosuppression, impairing the efficacy of immunotherapy against HPV+ cancers
Gabriele Galliverti, Stephan Wullschleger, Mélanie Tichet, Dhaarini Murugan, Nadine Zangger, Wesley Horton, Alan J Korman, Lisa M. Coussens, Melody A. Swartz and Douglas Hanahan
Cancer Immunol Res November 26 2019 DOI: 10.1158/2326-6066.CIR-19-0315
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Cancer Immunology Research
eISSN: 2326-6074
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