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Cancer Immunology, Immunotherapy

, Volume 67, Issue 2, pp 183–193 | Cite as

A filamentous bacteriophage targeted to carcinoembryonic antigen induces tumor regression in mouse models of colorectal cancer

  • Paola Murgas
  • Nicolás Bustamante
  • Nicole Araya
  • Sebastián Cruz-Gómez
  • Eduardo Durán
  • Diana Gaete
  • César Oyarce
  • Ernesto López
  • Andrés Alonso Herrada
  • Nicolás Ferreira
  • Hans Pieringer
  • Alvaro Lladser
Original Article

Abstract

Colorectal cancer is a deadly disease, which is frequently diagnosed at advanced stages, where conventional treatments are no longer effective. Cancer immunotherapy has emerged as a new form to treat different malignancies by turning-on the immune system against tumors. However, tumors are able to evade antitumor immune responses by promoting an immunosuppressive microenvironment. Single-stranded DNA containing M13 bacteriophages are highly immunogenic and can be specifically targeted to the surface of tumor cells to trigger inflammation and infiltration of activated innate immune cells, overcoming tumor-associated immunosuppression and promoting antitumor immunity. Carcinoembryonic antigen (CEA) is highly expressed in colorectal cancers and has been shown to promote several malignant features of colorectal cancer cells. In this work, we targeted M13 bacteriophage to CEA, a tumor-associated antigen over-expressed in a high proportion of colorectal cancers but largely absent in normal cells. The CEA-targeted M13 bacteriophage was shown to specifically bind to purified CEA and CEA-expressing tumor cells in vitro. Both intratumoral and systemic administration of CEA-specific bacteriophages significantly reduced tumor growth of mouse models of colorectal cancer, as compared to PBS and control bacteriophage administration. CEA-specific bacteriophages promoted tumor infiltration of neutrophils and macrophages, as well as maturation dendritic cells in tumor-draining lymph nodes, suggesting that antitumor T-cell responses were elicited. Finally, we demonstrated that tumor protection provided by CEA-specific bacteriophage particles is mediated by CD8+ T cells, as depletion of circulating CD8+ T cells completely abrogated antitumor protection. In summary, we demonstrated that CEA-specific M13 bacteriophages represent a potential immunotherapy against colorectal cancer.

Keywords

Colorectal cancer Bacteriophages Carcinoembryonic antigen Cancer immunotherapy 

Abbreviations

αCEA

Carcinoembryonic antigen-specific

CEA

Carcinoembryonic antigen

CRC

Colorectal cancer

TAM

Tumor-associated macrophages

TAN

Tumor-associated neutrophils

WT

Wild-type

Notes

Compliance with ethical standards

Conflict of interest

Nicolas Ferreira and Hans Pieringer are founders of and work for Phage Technologies S.A. All other authors declare that they have no conflict of interest.

Funding

This work was funded by Grants CONICYT PFB-16 and CONICYT-791100038 (to Alvaro Lladser) from “Comisión Nacional de Investigación Científica y Tecnológica de Chile”; FONDECYT-1171703 (to Alvaro Lladser) and FONDECYT-3130764 (to Paola Murgas) from “Fondo Nacional de Desarrollo Científico y Tecnológico de Chile”; CORFO-INNOVA 12IDL2-13348 (to Alvaro Lladser) from “Corporación de Fomento de la Producción de Chile”.

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Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Paola Murgas
    • 1
  • Nicolás Bustamante
    • 1
  • Nicole Araya
    • 1
  • Sebastián Cruz-Gómez
    • 1
  • Eduardo Durán
    • 1
  • Diana Gaete
    • 1
  • César Oyarce
    • 1
  • Ernesto López
    • 1
  • Andrés Alonso Herrada
    • 1
  • Nicolás Ferreira
    • 2
  • Hans Pieringer
    • 2
  • Alvaro Lladser
    • 1
  1. 1.Laboratory of Gene ImmunotherapyFundación Ciencia & VidaSantiagoChile
  2. 2.Phage TechnologiesSantiagoChile

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