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research article

Myeloid Cells Orchestrate Systemic Immunosuppression, Impairing the Efficacy of Immunotherapy against HPV+ Cancers

Galliverti, Gabriele  
•
Wullschleger, Stephan  
•
Tichet, Melanie  
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January 1, 2020
Cancer Immunology Research

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 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. 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 CD8(+) 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 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 antitumor immune responses.

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Type
research article
DOI
10.1158/2326-6066.CIR-19-0315
Web of Science ID

WOS:000505667700013

Author(s)
Galliverti, Gabriele  
•
Wullschleger, Stephan  
•
Tichet, Melanie  
•
Murugan, Dhaarini
•
Zangger, Nadine  
•
Horton, Wesley
•
Korman, Alan J.
•
Coussens, Lisa M.
•
Swartz, Melody A.
•
Hanahan, Douglas  
Date Issued

2020-01-01

Publisher

AMER ASSOC CANCER RESEARCH

Published in
Cancer Immunology Research
Volume

8

Issue

1

Start page

131

End page

145

Subjects

Oncology

•

Immunology

•

suppressor-cells

•

t-cells

•

squamous carcinogenesis

•

antitumor-activity

•

natural-history

•

expression

•

persistence

•

antibodies

•

immunity

•

burden

Peer reviewed

REVIEWED

Written at

EPFL

EPFL units
CMSO  
Available on Infoscience
March 3, 2020
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/166877
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