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Tumorous expression of NAC1 restrains antitumor immunity through the LDHA-mediated immune evasion
BACKGROUND: T cell-mediated antitumor immunity has a vital role in cancer prevention and treatment; however, the immune-suppressive tumor microenvironment (TME) constitutes a significant contributor to immune evasion that weakens antitumor immunity. Here, we explore the relationship between nucleus...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9511653/ https://www.ncbi.nlm.nih.gov/pubmed/36150745 http://dx.doi.org/10.1136/jitc-2022-004856 |
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author | Ren, Yijie Kumar, Anil Das, Jugal K Peng, Hao-Yun Wang, Liqing Balllard, Darby Xiong, Xiaofang Ren, Xingcong Zhang, Yi Yang, Jin-Ming Song, Jianxun |
author_facet | Ren, Yijie Kumar, Anil Das, Jugal K Peng, Hao-Yun Wang, Liqing Balllard, Darby Xiong, Xiaofang Ren, Xingcong Zhang, Yi Yang, Jin-Ming Song, Jianxun |
author_sort | Ren, Yijie |
collection | PubMed |
description | BACKGROUND: T cell-mediated antitumor immunity has a vital role in cancer prevention and treatment; however, the immune-suppressive tumor microenvironment (TME) constitutes a significant contributor to immune evasion that weakens antitumor immunity. Here, we explore the relationship between nucleus accumbens-associated protein-1 (NAC1), a nuclear factor of the BTB (broad-complex, Tramtrack, bric a brac)/POZ (Poxvirus, and Zinc finger) gene family, and the TME. METHODS: Adoptive cell transfer (ACT) of mouse or human tumor antigen (Ag)-specific CD8(+) cytotoxic T lymphocytes (CTLs) was tested in an immunocompetent or immunodeficient mouse model of melanoma with or without expression of NAC1. The effects of NAC1 expression on immune evasion in tumor cells were assessed in vitro and in vivo. CRISPR/Cas9, glycolysis analysis, retroviral transduction, quantitative real-time PCR, flow cytometric analysis, immunoblotting, database analyses were used to screen the downstream target and underlying mechanism of NAC1 in tumor cells. RESULTS: Tumorous expression of NAC1 negatively impacts the CTL-mediated antitumor immunity via lactate dehydrogenase A (LDHA)-mediated suppressive TME. NAC1 positively regulated the expression of LDHA at the transcriptional level, which led to higher accumulation of lactic acid in the TME. This inhibited the cytokine production and induced exhaustion and apoptosis of CTLs, impairing their cell-killing ability. In the immunocompetent and immunodeficient mice, NAC1 depleted melanoma tumors grew significantly slower and had an elevated infiltration of tumor Ag-specific CTLs following ACT, compared with the control groups. CONCLUSIONS: Tumor expression of NAC1 contributes substantially to immune evasion through its regulatory role in LDHA expression and lactic acid production. Thus, therapeutic targeting of NAC1 warrants further exploration as a potential strategy to reinforce cancer immunotherapy, such as the ACT of CTLs. |
format | Online Article Text |
id | pubmed-9511653 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-95116532022-09-27 Tumorous expression of NAC1 restrains antitumor immunity through the LDHA-mediated immune evasion Ren, Yijie Kumar, Anil Das, Jugal K Peng, Hao-Yun Wang, Liqing Balllard, Darby Xiong, Xiaofang Ren, Xingcong Zhang, Yi Yang, Jin-Ming Song, Jianxun J Immunother Cancer Basic Tumor Immunology BACKGROUND: T cell-mediated antitumor immunity has a vital role in cancer prevention and treatment; however, the immune-suppressive tumor microenvironment (TME) constitutes a significant contributor to immune evasion that weakens antitumor immunity. Here, we explore the relationship between nucleus accumbens-associated protein-1 (NAC1), a nuclear factor of the BTB (broad-complex, Tramtrack, bric a brac)/POZ (Poxvirus, and Zinc finger) gene family, and the TME. METHODS: Adoptive cell transfer (ACT) of mouse or human tumor antigen (Ag)-specific CD8(+) cytotoxic T lymphocytes (CTLs) was tested in an immunocompetent or immunodeficient mouse model of melanoma with or without expression of NAC1. The effects of NAC1 expression on immune evasion in tumor cells were assessed in vitro and in vivo. CRISPR/Cas9, glycolysis analysis, retroviral transduction, quantitative real-time PCR, flow cytometric analysis, immunoblotting, database analyses were used to screen the downstream target and underlying mechanism of NAC1 in tumor cells. RESULTS: Tumorous expression of NAC1 negatively impacts the CTL-mediated antitumor immunity via lactate dehydrogenase A (LDHA)-mediated suppressive TME. NAC1 positively regulated the expression of LDHA at the transcriptional level, which led to higher accumulation of lactic acid in the TME. This inhibited the cytokine production and induced exhaustion and apoptosis of CTLs, impairing their cell-killing ability. In the immunocompetent and immunodeficient mice, NAC1 depleted melanoma tumors grew significantly slower and had an elevated infiltration of tumor Ag-specific CTLs following ACT, compared with the control groups. CONCLUSIONS: Tumor expression of NAC1 contributes substantially to immune evasion through its regulatory role in LDHA expression and lactic acid production. Thus, therapeutic targeting of NAC1 warrants further exploration as a potential strategy to reinforce cancer immunotherapy, such as the ACT of CTLs. BMJ Publishing Group 2022-09-23 /pmc/articles/PMC9511653/ /pubmed/36150745 http://dx.doi.org/10.1136/jitc-2022-004856 Text en © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) . |
spellingShingle | Basic Tumor Immunology Ren, Yijie Kumar, Anil Das, Jugal K Peng, Hao-Yun Wang, Liqing Balllard, Darby Xiong, Xiaofang Ren, Xingcong Zhang, Yi Yang, Jin-Ming Song, Jianxun Tumorous expression of NAC1 restrains antitumor immunity through the LDHA-mediated immune evasion |
title | Tumorous expression of NAC1 restrains antitumor immunity through the LDHA-mediated immune evasion |
title_full | Tumorous expression of NAC1 restrains antitumor immunity through the LDHA-mediated immune evasion |
title_fullStr | Tumorous expression of NAC1 restrains antitumor immunity through the LDHA-mediated immune evasion |
title_full_unstemmed | Tumorous expression of NAC1 restrains antitumor immunity through the LDHA-mediated immune evasion |
title_short | Tumorous expression of NAC1 restrains antitumor immunity through the LDHA-mediated immune evasion |
title_sort | tumorous expression of nac1 restrains antitumor immunity through the ldha-mediated immune evasion |
topic | Basic Tumor Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9511653/ https://www.ncbi.nlm.nih.gov/pubmed/36150745 http://dx.doi.org/10.1136/jitc-2022-004856 |
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