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Human hydatid cyst fluid-induced therapeutic anti-cancer immune responses via NK1.1+ cell activation in mice

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Abstract

Echinococcus granulosus is a cestode parasite which causes cystic echinococcosis disease. Previously we observed that vaccination with E. granulosus antigens from human hydatid cyst fluid (HCF) significantly inhibits colon cancer growth. In the present work, we evaluate the anti-tumor immune response induced by human HCF against LL/2 lung cancer in mice. HCF vaccination protected from tumor growth, both in prophylactic and therapeutic settings, and significantly increased mouse survival compared to control mice. Considering that tumor-associated carbohydrate antigens are expressed in E. granulosus, we oxidized terminal carbohydrates in HCF with sodium periodate. This treatment abrogates the anti-tumor activity induced by HCF vaccination. We found that HCF vaccination-induced IgG antibodies that recognize LL/2 tumor cells by flow cytometry. An antigen-specific immune response is induced with HCF vaccination in the tumor-draining lymph nodes and spleen characterized by the production of IL-5 and, in less extent, IFNɣ. In the tumor microenvironment, we found that NK1.1 positive cells from HCF-treated mice showed higher expression of CD69 than control mice ones, indicating a higher level of activation. When we depleted these cells by administrating the NK-specific antibody NK1.1, a significantly decreased survival was observed in HCF-induced mice, suggesting that NK1.1+ cells mediate the anti-tumor protection induced by HCF. These results suggest that HCF can evoke an integrated anti-tumor immune response involving both, the innate and adaptive components, and provide novel insights into the understanding of the intricate relationship between HCF vaccination and tumor growth.

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Acknowledgements

We thank the Flow Cytometry Facility of Institut Pasteur de Montevideo for their assistance.

Funding

This work was supported by Fondo María Viñas, Agencia Nacional de Investigación e Innovación, Uruguay [Number FMV_1_2017_1_136442] (to EO), Fondo ANII-GSK, Agencia Nacional de Investigación e Innovación, Uruguay [Number FSGSK_1_2017_1_145466] (to EO), Programa Grupos de Investigación, CSIC, Universidad de la República, Uruguay [number 908] (to EO), Fondo para la Convergencia Estructural del MERCOSUR [COF 03/11] (to EB, GFG, MC, NB and EO).

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Author notes

  1. Edgardo Berriel and Teresa Freire have contributed equally to this work.

Authors and Affiliations

  1. Laboratorio de Glicobiología e Inmunología Tumoral, Institut Pasteur de Montevideo, 11400, Montevideo, CP, Uruguay

    Edgardo Berriel, Nora Berois & Eduardo Osinaga

  2. Clínica Quirúrgica 1, Hospital Pasteur, Facultad de Medicina, Universidad de La República, Montevideo, Uruguay

    Edgardo Berriel

  3. Departamento de Inmunobiología, Facultad de Medicina, Universidad de La República, Avda Gral Flores 2125, 11800, Montevideo, CP, Uruguay

    Teresa Freire, Carolina Chiale, Ernesto Rodríguez & Eduardo Osinaga

  4. Facultad de Ciencias Químicas, Centro de Investigaciones en Bioquímica Clínica e Inmunología, Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad Nacional de Córdoba, Córdoba, Argentina

    Gabriel Morón

  5. Unidad de Animales Transgénicos y Experimentación (UATE), Institut Pasteur de Montevideo, Montevideo, Uruguay

    Gabriel Fernández-Graña & Martina Crispo

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  1. Edgardo Berriel
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Contributions

EO, TF, and EB designed the study. EB, TF, CC, ER, GFG, and NB performed experiments and analyzing the data. MC, GM and EO contributed to analysis and interpretation. TF, EO, and EB analyzed the data and wrote the manuscript. GM, NB and MC critically revised the manuscript. All authors approved the manuscript.

Corresponding author

Correspondence to Eduardo Osinaga.

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The authors declare that they have no conflict of interest.

Ethical approval

All mice were maintained under specific pathogen-free conditions and used in accordance with protocols established by the Animal Care Committee of the Institut Pasteur de Montevideo, Uruguay. All work with mice was performed according to protocol # 010/12 approved by the Institutional Animal Care Committee and following the National Law of Animal Experimentation (# 18.611).

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Berriel, E., Freire, T., Chiale, C. et al. Human hydatid cyst fluid-induced therapeutic anti-cancer immune responses via NK1.1+ cell activation in mice. Cancer Immunol Immunother 70, 3617–3627 (2021). https://doi.org/10.1007/s00262-021-02948-x

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