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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Main Authors:	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
Format:	Online
Language:	English
Published:	Public Library of Science 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684241/

id	pubmed-4684241
recordtype	oai_dc
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 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.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
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
spellingShingle	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
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
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_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_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_sort	immunocompetent mouse model for mll/af9 leukemia reveals the potential of spontaneous cytotoxic t-cell response to an antigen expressed in leukemia cells
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.
publisher	Public Library of Science
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684241/
_version_	1613514475957125120

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

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