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Inhibition of LDH-A by Oxamate Enhances the Efficacy of Anti-PD-1 Treatment in an NSCLC Humanized Mouse Model

Immunotherapy is a curable treatment for certain cancers, but it is still only effective in a small subset of patients, partly because of the lack of sufficient immune cells in the tumor. It is reported that targeted lactate dehydrogenase (LDH) to reduce lactic acid production can promote the infilt...

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Autores principales: Qiao, Tianyun, Xiong, Yanlu, Feng, Yangbo, Guo, Wenwen, Zhou, Yongsheng, Zhao, Jinbo, Jiang, Tao, Shi, Changhong, Han, Yong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042335/
https://www.ncbi.nlm.nih.gov/pubmed/33859941
http://dx.doi.org/10.3389/fonc.2021.632364
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author Qiao, Tianyun
Xiong, Yanlu
Feng, Yangbo
Guo, Wenwen
Zhou, Yongsheng
Zhao, Jinbo
Jiang, Tao
Shi, Changhong
Han, Yong
author_facet Qiao, Tianyun
Xiong, Yanlu
Feng, Yangbo
Guo, Wenwen
Zhou, Yongsheng
Zhao, Jinbo
Jiang, Tao
Shi, Changhong
Han, Yong
author_sort Qiao, Tianyun
collection PubMed
description Immunotherapy is a curable treatment for certain cancers, but it is still only effective in a small subset of patients, partly because of the lack of sufficient immune cells in the tumor. It is reported that targeted lactate dehydrogenase (LDH) to reduce lactic acid production can promote the infiltration and activity of immune cells and turn tumors into hot tumors. Therefore, we constructed a humanized mouse model to evaluate the efficacy of using classical LDH inhibitor oxamate and pembrolizumab alone or in combination in non-small cell lung cancer (NSCLC). We found that both oxamate and pembrolizumab monotherapy significantly delayed tumor growth; moreover, combination therapy showed better results. Immunofluorescence analysis showed that oxamate treatment increased the infiltration of activated CD8+ T cells in the tumor, which might have enhanced the therapeutic effects of pembrolizumab. Treatment of the humanized mice with anti-CD8 abrogated the therapeutic effects of oxamate, indicating CD8+ T cells as the main force mediating the effect of oxamate. In conclusion, Our preclinical findings position that oxamate not only inhibits tumor growth at a high safe dose but also enhances the efficacy of pembrolizumab in Hu-PBMC-CDX mice. Our study also provides a preclinical model for exploring the efficacy of other immune-based combination therapies for NSCLC.
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spelling pubmed-80423352021-04-14 Inhibition of LDH-A by Oxamate Enhances the Efficacy of Anti-PD-1 Treatment in an NSCLC Humanized Mouse Model Qiao, Tianyun Xiong, Yanlu Feng, Yangbo Guo, Wenwen Zhou, Yongsheng Zhao, Jinbo Jiang, Tao Shi, Changhong Han, Yong Front Oncol Oncology Immunotherapy is a curable treatment for certain cancers, but it is still only effective in a small subset of patients, partly because of the lack of sufficient immune cells in the tumor. It is reported that targeted lactate dehydrogenase (LDH) to reduce lactic acid production can promote the infiltration and activity of immune cells and turn tumors into hot tumors. Therefore, we constructed a humanized mouse model to evaluate the efficacy of using classical LDH inhibitor oxamate and pembrolizumab alone or in combination in non-small cell lung cancer (NSCLC). We found that both oxamate and pembrolizumab monotherapy significantly delayed tumor growth; moreover, combination therapy showed better results. Immunofluorescence analysis showed that oxamate treatment increased the infiltration of activated CD8+ T cells in the tumor, which might have enhanced the therapeutic effects of pembrolizumab. Treatment of the humanized mice with anti-CD8 abrogated the therapeutic effects of oxamate, indicating CD8+ T cells as the main force mediating the effect of oxamate. In conclusion, Our preclinical findings position that oxamate not only inhibits tumor growth at a high safe dose but also enhances the efficacy of pembrolizumab in Hu-PBMC-CDX mice. Our study also provides a preclinical model for exploring the efficacy of other immune-based combination therapies for NSCLC. Frontiers Media S.A. 2021-03-30 /pmc/articles/PMC8042335/ /pubmed/33859941 http://dx.doi.org/10.3389/fonc.2021.632364 Text en Copyright © 2021 Qiao, Xiong, Feng, Guo, Zhou, Zhao, Jiang, Shi and Han https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Qiao, Tianyun
Xiong, Yanlu
Feng, Yangbo
Guo, Wenwen
Zhou, Yongsheng
Zhao, Jinbo
Jiang, Tao
Shi, Changhong
Han, Yong
Inhibition of LDH-A by Oxamate Enhances the Efficacy of Anti-PD-1 Treatment in an NSCLC Humanized Mouse Model
title Inhibition of LDH-A by Oxamate Enhances the Efficacy of Anti-PD-1 Treatment in an NSCLC Humanized Mouse Model
title_full Inhibition of LDH-A by Oxamate Enhances the Efficacy of Anti-PD-1 Treatment in an NSCLC Humanized Mouse Model
title_fullStr Inhibition of LDH-A by Oxamate Enhances the Efficacy of Anti-PD-1 Treatment in an NSCLC Humanized Mouse Model
title_full_unstemmed Inhibition of LDH-A by Oxamate Enhances the Efficacy of Anti-PD-1 Treatment in an NSCLC Humanized Mouse Model
title_short Inhibition of LDH-A by Oxamate Enhances the Efficacy of Anti-PD-1 Treatment in an NSCLC Humanized Mouse Model
title_sort inhibition of ldh-a by oxamate enhances the efficacy of anti-pd-1 treatment in an nsclc humanized mouse model
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042335/
https://www.ncbi.nlm.nih.gov/pubmed/33859941
http://dx.doi.org/10.3389/fonc.2021.632364
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