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

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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.

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Abbreviations

αCEA:

Carcinoembryonic antigen-specific

CEA:

Carcinoembryonic antigen

CRC:

Colorectal cancer

TAM:

Tumor-associated macrophages

TAN:

Tumor-associated neutrophils

WT:

Wild-type

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Authors and Affiliations

  1. Laboratory of Gene Immunotherapy, Fundación Ciencia & Vida, Av. Zañartu 1482, Ñuñoa, 7780272, Santiago, Chile

    Paola Murgas, Nicolás Bustamante, Nicole Araya, Sebastián Cruz-Gómez, Eduardo Durán, Diana Gaete, César Oyarce, Ernesto López, Andrés Alonso Herrada & Alvaro Lladser

  2. Phage Technologies, Parque Tecnológico Zañartu, Av. Zañartu 1482, Ñuñoa, 7780272, Santiago, Chile

    Nicolás Ferreira & Hans Pieringer

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  1. Paola Murgas
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  2. Nicolás Bustamante
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Correspondence to Alvaro Lladser.

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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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Murgas, P., Bustamante, N., Araya, N. et al. A filamentous bacteriophage targeted to carcinoembryonic antigen induces tumor regression in mouse models of colorectal cancer. Cancer Immunol Immunother 67, 183–193 (2018). https://doi.org/10.1007/s00262-017-2076-x

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  • DOI: https://doi.org/10.1007/s00262-017-2076-x

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