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Anti-PD-1 inhibits Foxp3+ Treg cell conversion and unleashes intratumoural effector T cells thereby enhancing the efficacy of a cancer vaccine in a mouse model

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Abstract

The co-inhibitory molecule PD-1 suppresses T cell responses and has been targeted in the treatment of cancer. Here, we examined the role of PD-1 in regulating the balance between regulatory and effector T cells and whether blocking PD-1 could enhance tumour vaccine-induced protective immunity. A significantly higher proportion of tumour-resident T cells expressed PD-1 and Foxp3 compared with T cells in the tumour circulation or draining lymph nodes, and this correlated with a lower frequency of IFN-γ- and TNF-secreting CD8 T cells. Blocking PD-1 with a specific antibody reduced Foxp3+ regulatory T (Treg) cell induction and enhanced proliferation, cytokine production, and tumour killing by CD8 T cells. Treatment of CT26 tumour-bearing mice with anti-PD-1 in combination with a vaccine, comprising heat-shocked irradiated tumour cells and a TLR 7/8 agonist, significantly reduced tumour growth and enhanced survival. Furthermore, surviving mice resisted tumour re-challenge. The rejection of tumours in mice treated with the anti-PD-1 vaccine combination was associated with a reduction in tumour-infiltrating Treg cells and enhancement of IFN-γ-secreting CD8 T cells. Our findings demonstrate that high PD-1 expression correlates with increased tumour-infiltrating Treg cells and reduced effector T cells and that when combined with a potent antigen-adjuvant combination, blocking PD-1 effectively enhances anti-tumour immunity.

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Abbreviations

BFA:

Brefeldin A

CTV:

CellTrace Violet

dLN:

Draining lymph nodes

hs:

Heat-shocked

irr:

γ-Irradiated

RA:

Retinoic acid

Treg cells:

Regulatory T cells

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Acknowledgments

This work was supported by a Science Foundation Ireland Principal investigator Grant (#11/PI/1036) to Kingston H. G. Mills.

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Authors and Affiliations

  1. Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, Ireland

    Lydia Dyck, Mieszko M. Wilk, Mathilde Raverdeau, Alicja Misiak & Kingston H. G. Mills

  2. Bioceros, Utrecht, The Netherlands

    Louis Boon

Authors
  1. Lydia Dyck
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  2. Mieszko M. Wilk
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  3. Mathilde Raverdeau
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  4. Alicja Misiak
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  5. Louis Boon
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  6. Kingston H. G. Mills
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Correspondence to Kingston H. G. Mills.

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Conflict of interest

Kingston H. G. Mills is a co-founder and shareholder in Opsona Therapeutics Ltd and TriMod Therapeutics Ltd, university spin-out companies involved in the development of immunotherapeutics. All other authors do not have any conflict of interest.

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Dyck, L., Wilk, M.M., Raverdeau, M. et al. Anti-PD-1 inhibits Foxp3+ Treg cell conversion and unleashes intratumoural effector T cells thereby enhancing the efficacy of a cancer vaccine in a mouse model. Cancer Immunol Immunother 65, 1491–1498 (2016). https://doi.org/10.1007/s00262-016-1906-6

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  • DOI: https://doi.org/10.1007/s00262-016-1906-6

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