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An Immunocompetent Mouse Model for MLL/AF9 Leukemia Reveals the Potential of Spontaneous Cytotoxic T-Cell Response to an Antigen Expressed in Leukemia Cells

Leukemia differs substantially with respect to stromal milieu from tumors that progress locally as solid masses, and the physiological importance of immunosurveillance in leukemia remains unclear. However, currently available mouse leukemia models have critical limitations in the context of analyzin...

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Autores principales: Hasegawa, Kana, Tanaka, Satomi, Fujiki, Fumihiro, Morimoto, Soyoko, Nakajima, Hiroko, Tatsumi, Naoya, Nakata, Jun, Takashima, Satoshi, Nishida, Sumiyuki, Tsuboi, Akihiro, Oka, Yoshihiro, Oji, Yusuke, Kumanogoh, Atsushi, Sugiyama, Haruo, Hosen, Naoki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684241/
https://www.ncbi.nlm.nih.gov/pubmed/26658107
http://dx.doi.org/10.1371/journal.pone.0144594
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author Hasegawa, Kana
Tanaka, Satomi
Fujiki, Fumihiro
Morimoto, Soyoko
Nakajima, Hiroko
Tatsumi, Naoya
Nakata, Jun
Takashima, Satoshi
Nishida, Sumiyuki
Tsuboi, Akihiro
Oka, Yoshihiro
Oji, Yusuke
Kumanogoh, Atsushi
Sugiyama, Haruo
Hosen, Naoki
author_facet Hasegawa, Kana
Tanaka, Satomi
Fujiki, Fumihiro
Morimoto, Soyoko
Nakajima, Hiroko
Tatsumi, Naoya
Nakata, Jun
Takashima, Satoshi
Nishida, Sumiyuki
Tsuboi, Akihiro
Oka, Yoshihiro
Oji, Yusuke
Kumanogoh, Atsushi
Sugiyama, Haruo
Hosen, Naoki
author_sort Hasegawa, Kana
collection PubMed
description Leukemia differs substantially with respect to stromal milieu from tumors that progress locally as solid masses, and the physiological importance of immunosurveillance in leukemia remains unclear. However, currently available mouse leukemia models have critical limitations in the context of analyzing immunological regulation of leukemia development. In this study, we transferred mouse MLL/AF9 leukemia-initiating cells into immunocompetent recipient mice without any pre-conditioning such as irradiation, and then analyzed the spontaneous T cell response to an immunogenic antigen expressed in leukemia cells. When the minimum numbers of leukemia-initiating cells for engraftment were transferred, leukemia cells were eradicated by the adaptive immune response in most, if not all, wild-type mice, but not in Rag2 (-/-) recipient mice, which lack adaptive immunity. By contrast, mice transplanted with larger numbers of leukemia cells always developed leukemia. In mice with advanced leukemia, antigen-specific CTLs were also expanded, but were unresponsive to antigen stimulation and expressed high levels of PD-1 and LAG-3. These results provide the first clear demonstration that the spontaneous CTL response to a tumor-cell antigen has the potential to eradicate leukemia, whereas antigen-specific CTLs are exhausted in animals with advanced leukemia. This immunocompetent mouse leukemia model provides a useful platform for developing effective immunotherapies against leukemia.
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spelling pubmed-46842412015-12-31 An Immunocompetent Mouse Model for MLL/AF9 Leukemia Reveals the Potential of Spontaneous Cytotoxic T-Cell Response to an Antigen Expressed in Leukemia Cells Hasegawa, Kana Tanaka, Satomi Fujiki, Fumihiro Morimoto, Soyoko Nakajima, Hiroko Tatsumi, Naoya Nakata, Jun Takashima, Satoshi Nishida, Sumiyuki Tsuboi, Akihiro Oka, Yoshihiro Oji, Yusuke Kumanogoh, Atsushi Sugiyama, Haruo Hosen, Naoki PLoS One Research Article Leukemia differs substantially with respect to stromal milieu from tumors that progress locally as solid masses, and the physiological importance of immunosurveillance in leukemia remains unclear. However, currently available mouse leukemia models have critical limitations in the context of analyzing immunological regulation of leukemia development. In this study, we transferred mouse MLL/AF9 leukemia-initiating cells into immunocompetent recipient mice without any pre-conditioning such as irradiation, and then analyzed the spontaneous T cell response to an immunogenic antigen expressed in leukemia cells. When the minimum numbers of leukemia-initiating cells for engraftment were transferred, leukemia cells were eradicated by the adaptive immune response in most, if not all, wild-type mice, but not in Rag2 (-/-) recipient mice, which lack adaptive immunity. By contrast, mice transplanted with larger numbers of leukemia cells always developed leukemia. In mice with advanced leukemia, antigen-specific CTLs were also expanded, but were unresponsive to antigen stimulation and expressed high levels of PD-1 and LAG-3. These results provide the first clear demonstration that the spontaneous CTL response to a tumor-cell antigen has the potential to eradicate leukemia, whereas antigen-specific CTLs are exhausted in animals with advanced leukemia. This immunocompetent mouse leukemia model provides a useful platform for developing effective immunotherapies against leukemia. Public Library of Science 2015-12-11 /pmc/articles/PMC4684241/ /pubmed/26658107 http://dx.doi.org/10.1371/journal.pone.0144594 Text en © 2015 Hasegawa et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Hasegawa, Kana
Tanaka, Satomi
Fujiki, Fumihiro
Morimoto, Soyoko
Nakajima, Hiroko
Tatsumi, Naoya
Nakata, Jun
Takashima, Satoshi
Nishida, Sumiyuki
Tsuboi, Akihiro
Oka, Yoshihiro
Oji, Yusuke
Kumanogoh, Atsushi
Sugiyama, Haruo
Hosen, Naoki
An Immunocompetent Mouse Model for MLL/AF9 Leukemia Reveals the Potential of Spontaneous Cytotoxic T-Cell Response to an Antigen Expressed in Leukemia Cells
title An Immunocompetent Mouse Model for MLL/AF9 Leukemia Reveals the Potential of Spontaneous Cytotoxic T-Cell Response to an Antigen Expressed in Leukemia Cells
title_full An Immunocompetent Mouse Model for MLL/AF9 Leukemia Reveals the Potential of Spontaneous Cytotoxic T-Cell Response to an Antigen Expressed in Leukemia Cells
title_fullStr An Immunocompetent Mouse Model for MLL/AF9 Leukemia Reveals the Potential of Spontaneous Cytotoxic T-Cell Response to an Antigen Expressed in Leukemia Cells
title_full_unstemmed An Immunocompetent Mouse Model for MLL/AF9 Leukemia Reveals the Potential of Spontaneous Cytotoxic T-Cell Response to an Antigen Expressed in Leukemia Cells
title_short An Immunocompetent Mouse Model for MLL/AF9 Leukemia Reveals the Potential of Spontaneous Cytotoxic T-Cell Response to an Antigen Expressed in Leukemia Cells
title_sort immunocompetent mouse model for mll/af9 leukemia reveals the potential of spontaneous cytotoxic t-cell response to an antigen expressed in leukemia cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684241/
https://www.ncbi.nlm.nih.gov/pubmed/26658107
http://dx.doi.org/10.1371/journal.pone.0144594
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