NANOG confers resistance to complement-dependent cytotoxicity in immune-edited tumor cells through up-regulating CD59

Sung Wook Son; Eunho Cho; Hanbyoul Cho; Seon Rang Woo; Hyo Jung Lee; Se Jin Oh; Suyeon Kim; Jae Hoon Kim; Eun Joo Chung; Joon Yong Chung; Min Gyu Kim; Kwon Ho Song; Tae Woo Kim

doi:10.1038/s41598-022-12692-6

NANOG confers resistance to complement-dependent cytotoxicity in immune-edited tumor cells through up-regulating CD59

Sung Wook Son, Eunho Cho, Hanbyoul Cho, Seon Rang Woo, Hyo Jung Lee, Se Jin Oh, Suyeon Kim, Jae Hoon Kim, Eun Joo Chung, Joon Yong Chung, Min Gyu Kim, Kwon Ho Song, Tae Woo Kim

Department of Obstetrics and Gynecology

Research output: Contribution to journal › Article › peer-review

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Abstract

Cancer immunoediting drives the adaptation of tumor cells to host immune surveillance. Previously, we have demonstrated that immunoediting driven by cytotoxic T lymphocytes (CTLs) enriches NANOG⁺ tumor cells with immune-refractory properties. Here, we found that CTL-mediated immune pressure triggered cross-resistance of tumor cells to the complement system, a part of the innate immune system. In this process, NANOG upregulated the membrane-bound complement regulatory protein (mCRP) CD59 through promoter occupancy, thereby contributing to the resistance of tumor cells against complement-dependent cytotoxicity (CDC). Notably, targeting of NANOG sensitized the immune-refractory tumor cells to trastuzumab-mediated CDC. Collectively, our results revealed a possible mechanism through which selection imposed by T-cell based immunotherapy triggered complement-resistant phenotypes in the tumor microenvironment (TME), by establishing a firm molecular link between NANOG and CD59 in immune-edited tumor cells. We believe these results hold important implications for the clinical application of CDC-mediated therapeutic antibody.

Original language	English
Article number	8652
Journal	Scientific reports
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41598-022-12692-6
Publication status	Published - 2022 Dec

Bibliographical note

Funding Information:
Tissue microarrays (TMAs) constructed from a cohort of 386 formalin-fixed, paraffin-embedded tumor specimens and matched nonadjacent normal specimens, have been described previously. The study samples from 178 cervical cancer patients and 126 cervical intraepithelial neoplasia (CIN) patients obtained by surgical resection in Gangnam Severance Hospital between 1996 and 2010 were histologically confirmed by a pathologist. Some of the paraffin blocks were provided by the Korea Gynecologic Cancer Bank through the Bio & Medical Technology Development Program of the Ministry of Education, Science and Technology, Korea (NRF-2017M3A9B8069610). Tissue samples were collected from patients who had signed informed consent form. This study was approved by the Institutional Review Board of Gangnam Severance Hospital (IRB# 3-2014-0184; Seoul, South Korea) and was additionally approved by the Office of Human Subjects Research at the National Institutes of Health. All procedures were conducted in accordance with the guidelines of the Declaration of Helsinki.

Funding Information:
This work was supported by funding from the National Research Foundation of Korea (NRF-2020R1A2C1007157, NRF-2020R1A2B5B03095410 and NRF-2019R1A4A1029000).

Publisher Copyright:
© 2022, The Author(s).

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title = "NANOG confers resistance to complement-dependent cytotoxicity in immune-edited tumor cells through up-regulating CD59",

abstract = "Cancer immunoediting drives the adaptation of tumor cells to host immune surveillance. Previously, we have demonstrated that immunoediting driven by cytotoxic T lymphocytes (CTLs) enriches NANOG+ tumor cells with immune-refractory properties. Here, we found that CTL-mediated immune pressure triggered cross-resistance of tumor cells to the complement system, a part of the innate immune system. In this process, NANOG upregulated the membrane-bound complement regulatory protein (mCRP) CD59 through promoter occupancy, thereby contributing to the resistance of tumor cells against complement-dependent cytotoxicity (CDC). Notably, targeting of NANOG sensitized the immune-refractory tumor cells to trastuzumab-mediated CDC. Collectively, our results revealed a possible mechanism through which selection imposed by T-cell based immunotherapy triggered complement-resistant phenotypes in the tumor microenvironment (TME), by establishing a firm molecular link between NANOG and CD59 in immune-edited tumor cells. We believe these results hold important implications for the clinical application of CDC-mediated therapeutic antibody.",

author = "Son, {Sung Wook} and Eunho Cho and Hanbyoul Cho and Woo, {Seon Rang} and Lee, {Hyo Jung} and Oh, {Se Jin} and Suyeon Kim and Kim, {Jae Hoon} and Chung, {Eun Joo} and Chung, {Joon Yong} and Kim, {Min Gyu} and Song, {Kwon Ho} and Kim, {Tae Woo}",

note = "Funding Information: Tissue microarrays (TMAs) constructed from a cohort of 386 formalin-fixed, paraffin-embedded tumor specimens and matched nonadjacent normal specimens, have been described previously. The study samples from 178 cervical cancer patients and 126 cervical intraepithelial neoplasia (CIN) patients obtained by surgical resection in Gangnam Severance Hospital between 1996 and 2010 were histologically confirmed by a pathologist. Some of the paraffin blocks were provided by the Korea Gynecologic Cancer Bank through the Bio & Medical Technology Development Program of the Ministry of Education, Science and Technology, Korea (NRF-2017M3A9B8069610). Tissue samples were collected from patients who had signed informed consent form. This study was approved by the Institutional Review Board of Gangnam Severance Hospital (IRB# 3-2014-0184; Seoul, South Korea) and was additionally approved by the Office of Human Subjects Research at the National Institutes of Health. All procedures were conducted in accordance with the guidelines of the Declaration of Helsinki. Funding Information: This work was supported by funding from the National Research Foundation of Korea (NRF-2020R1A2C1007157, NRF-2020R1A2B5B03095410 and NRF-2019R1A4A1029000). Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41598-022-12692-6",

language = "English",

volume = "12",

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AU - Son, Sung Wook

AU - Cho, Eunho

AU - Cho, Hanbyoul

AU - Woo, Seon Rang

AU - Lee, Hyo Jung

AU - Oh, Se Jin

AU - Kim, Suyeon

AU - Kim, Jae Hoon

AU - Chung, Eun Joo

AU - Chung, Joon Yong

AU - Kim, Min Gyu

AU - Song, Kwon Ho

AU - Kim, Tae Woo

N1 - Funding Information: Tissue microarrays (TMAs) constructed from a cohort of 386 formalin-fixed, paraffin-embedded tumor specimens and matched nonadjacent normal specimens, have been described previously. The study samples from 178 cervical cancer patients and 126 cervical intraepithelial neoplasia (CIN) patients obtained by surgical resection in Gangnam Severance Hospital between 1996 and 2010 were histologically confirmed by a pathologist. Some of the paraffin blocks were provided by the Korea Gynecologic Cancer Bank through the Bio & Medical Technology Development Program of the Ministry of Education, Science and Technology, Korea (NRF-2017M3A9B8069610). Tissue samples were collected from patients who had signed informed consent form. This study was approved by the Institutional Review Board of Gangnam Severance Hospital (IRB# 3-2014-0184; Seoul, South Korea) and was additionally approved by the Office of Human Subjects Research at the National Institutes of Health. All procedures were conducted in accordance with the guidelines of the Declaration of Helsinki. Funding Information: This work was supported by funding from the National Research Foundation of Korea (NRF-2020R1A2C1007157, NRF-2020R1A2B5B03095410 and NRF-2019R1A4A1029000). Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - Cancer immunoediting drives the adaptation of tumor cells to host immune surveillance. Previously, we have demonstrated that immunoediting driven by cytotoxic T lymphocytes (CTLs) enriches NANOG+ tumor cells with immune-refractory properties. Here, we found that CTL-mediated immune pressure triggered cross-resistance of tumor cells to the complement system, a part of the innate immune system. In this process, NANOG upregulated the membrane-bound complement regulatory protein (mCRP) CD59 through promoter occupancy, thereby contributing to the resistance of tumor cells against complement-dependent cytotoxicity (CDC). Notably, targeting of NANOG sensitized the immune-refractory tumor cells to trastuzumab-mediated CDC. Collectively, our results revealed a possible mechanism through which selection imposed by T-cell based immunotherapy triggered complement-resistant phenotypes in the tumor microenvironment (TME), by establishing a firm molecular link between NANOG and CD59 in immune-edited tumor cells. We believe these results hold important implications for the clinical application of CDC-mediated therapeutic antibody.

AB - Cancer immunoediting drives the adaptation of tumor cells to host immune surveillance. Previously, we have demonstrated that immunoediting driven by cytotoxic T lymphocytes (CTLs) enriches NANOG+ tumor cells with immune-refractory properties. Here, we found that CTL-mediated immune pressure triggered cross-resistance of tumor cells to the complement system, a part of the innate immune system. In this process, NANOG upregulated the membrane-bound complement regulatory protein (mCRP) CD59 through promoter occupancy, thereby contributing to the resistance of tumor cells against complement-dependent cytotoxicity (CDC). Notably, targeting of NANOG sensitized the immune-refractory tumor cells to trastuzumab-mediated CDC. Collectively, our results revealed a possible mechanism through which selection imposed by T-cell based immunotherapy triggered complement-resistant phenotypes in the tumor microenvironment (TME), by establishing a firm molecular link between NANOG and CD59 in immune-edited tumor cells. We believe these results hold important implications for the clinical application of CDC-mediated therapeutic antibody.

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ER -

NANOG confers resistance to complement-dependent cytotoxicity in immune-edited tumor cells through up-regulating CD59

Abstract

Bibliographical note

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